Bone density, bone geometry
and bone development in
young men
The importance of pubertal timing and
fracture history
Anna Darelid
Department of Internal Medicine and Clinical Nutrition
Institute of Medicine
Sahlgrenska Academy at University of Gothenburg
Gothenburg 2015
Cover illustration: Image of the right hip assessed by DXA (Hologic
Discovery W)
Bone density, bone geometry and bone development in young men
© Anna Darelid 2015
[email protected]
ISBN 978-91-628-9300-2 (printed)
ISBN 978-91-628-9305-7 (epub)
http://hdl.handle.net/2077/38010
Printed in Gothenburg, Sweden 2015
Printed by Ineko AB
Till Martin
Bone density, bone geometry and bone development in
young men
The importance of pubertal timing and fracture history
ABSTRACT
Background and objective: Peak bone mass, the maximal bone mass attained in
young adulthood, is an important factor of the lifetime risk of developing
osteoporosis. The aim of this thesis was to study the development of bone mineral
density (BMD) and bone geometry around the time of peak bone mass in men, and
also to investigate the association between pubertal timing, fracture history, bone
turnover markers and BMD and bone geometry in young men.
Methods: The studies included in the thesis were performed within the Gothenburg
Osteoporosis and Obesity Determinants (GOOD) study, a well-characterized
population-based cohort including 1068 men between 18-20 years of age at baseline.
At baseline and follow-up five years later, measurements of bone density, bone mass
and bone geometry were assessed with dual energy X-ray absorptiometry (DXA) and
peripheral quantitative computed tomography (pQCT). Blood samples were drawn to
measure bone turnover markers. A self-administered questionnaire was used to
collect information about physical activity, nutritional intake, smoking and previous
fracture. Reported fractures were verified in X-ray registers.
Results: Previous fracture was associated with lower BMD at age 19, and especially
with reduced trabecular volumetric BMD (vBMD) of the radius. Between 19 and 24
years of age, lumbar spine areal BMD (aBMD) increased while femoral neck aBMD
decreased. Radius aBMD increased, due to increased cortical thickness and
continuing mineralization. Men with late puberty had larger gains in aBMD, vBMD,
and bone size, reflecting a catch up in bone acquisition in young adulthood in men
with late puberty. A high level of osteocalcin (a bone turnover marker) was
associated with larger gains in aBMD, vBMD, and bone size between 19 and 24
years.
Conclusion: In young adult men between 19 and 24 years, aBMD of the lumbar
spine and the radius continued to increase, while aBMD of the femoral neck already
started to decrease. Late puberty and high level of osteocalcin were associated with
greater increases in aBMD, vBMD and bone size during this period. A previous
fracture was a risk factor for low BMD in young men.
Keywords: peak bone mass, bone mineral density, bone development, fracture,
young adulthood, men
SAMMANFATTNING PÅ SVENSKA
Bakgrund: Den maximala benmassan (peak bone mass) som uppnås i ung vuxen
ålder, är en viktig faktor för risken att senare i livet drabbas av benskörhet
(osteoporos) och därmed ökad risk för benbrott (frakturer). En hög maximal
benmassa minskar risken för benskörhet.
Frågeställning: I den här avhandlingen studerades utvecklingen av benmassa,
bentäthet och benstorlek hos unga män vid tiden för maximal benmassa. Vi
undersökte om denna utveckling skilde sig åt beroende på tidpunkt för pubertet och
beroende på nivåer av benomsättningsmarkörer som kan mätas i blodprov. Vi
studerade också sambandet mellan fraktur under uppväxten och bentäthet och
benstorlek i ung vuxen ålder.
Metod: Delstudierna som ingår i avhandlingen utfördes inom en välkarakteriserad
populationsbaserad kohort bestående av 1068 unga män som vid studiens start var
mellan 18 och 20 år gamla (the Gothenburg Obesity and Osteoporosis Determinants
(GOOD) Study). Vid studiens början och vid uppföljningen fem år senare utfördes
mätningar av bentäthet, benmassa och benstorlek med hjälp av
dubbelfotonröntgenabsorbtiometri (DXA) och perifer kvantitativ datortomografi
(pQCT). Blodprov för mätning av benomsättningsmarkörer togs. Information om
fysisk aktivitet, näringsintag, rökning och frakturförekomst samlades in med hjälp av
frågeformulär. Förekomst av frakturer verifierades genom sökning i röntgenarkiv.
Resultat: Mellan 19 och 24 års ålder minskade bentätheten i höften medan den
ökade i ländryggen och radius (underarmen). De män som kommit i puberteten sent
hade lägre bentäthet vid 19 års ålder, men ökade mer i bentäthet mellan 19 och 24 års
ålder. Vid 24 års ålder hade män med sen pubertet kvarstående lägre bentäthet i
radius, men inte i höft eller ländrygg. Hög nivå av benomsättningsmarkören
osteocalcin vid 19 års ålder var kopplad till större ökning i bentäthet och benmassa
mellan 19 och 24 års ålder. De män som haft en fraktur under uppväxten hade vid 19
års ålder lägre bentäthet.
Slutsatser: I ung vuxen ålder (19-24 år) sågs hos män en fortsatt ökning av bentäthet
i ländrygg och radius, medan bentätheten i höften började sjunka. Sen pubertet och
hög nivå av osteocalcin var kopplat till större ökning av bentäthet och benstorlek
under den här perioden. Att ha haft en fraktur under uppväxten var en riskfaktor för
låg bentäthet hos unga män.
LIST OF PAPERS
This thesis is based on the following studies, referred to in the text by their
Roman numerals.
I.
Darelid A*, Ohlsson C*, Rudäng R, Kindblom JM,
Mellström D, Lorentzon M. Trabecular volumetric bone
mineral density is associated with previous fracture during
childhood and adolescence in males: the GOOD study. The
Journal of Bone and Mineral Research, March 2010;
25(3):537-544.
II.
Ohlsson C*, Darelid A*, Nilsson M, Melin J, Mellström D,
Lorentzon M. Cortical consolidation due to increased
mineralization and endosteal contraction in young adult
men: a five year longitudinal study. The Journal of Clinical
Endocrinology and Metabolism, July 2011; 96(7):22622269.
III.
Darelid A, Ohlsson C, Nilsson M, Kindblom JM, Mellström
D, Lorentzon M. Catch up in bone acquisition in young adult
men with late normal puberty. The Journal of Bone and
Mineral Research, October 2012; 27(10):2198-2207.
IV.
Darelid A, Nilsson M, Kindblom JM, Mellström D, Ohlsson
C, Lorentzon M. Bone turnover markers predict bone mass
development in young adult men: a five year longitudinal
study. The Journal of Clinical Endocrinology and
Metabolism, January 2015; epub before print.
*contributed equally
Reprints were made with permission from the publishers.
i
CONTENT
ABBREVIATIONS ............................................................................................. IV DEFINITIONS IN SHORT .................................................................................... V 1 INTRODUCTION ........................................................................................... 1 1.1 The skeleton and its functions ............................................................... 1 1.2 Bone structure ....................................................................................... 1 1.3 The bone cells........................................................................................ 2 1.4 Bone remodeling ................................................................................... 3 1.5 Osteoporosis and its consequences ....................................................... 4 1.6 Bone mineral accrual during growth ..................................................... 5 1.7 Peak bone mass ..................................................................................... 6 1.8 Determinants of peak bone mass ........................................................... 6 1.9 Pubertal timing and peak bone mass ..................................................... 8 1.10 Fractures during growth ........................................................................ 8 1.11 Bone turnover markers .......................................................................... 9 1.12 Techniques for measuring bone density .............................................. 10 1.12.1 Dual energy X-ray absorptiometry (DXA) .................................. 10 1.12.2 Peripheral quantitative computed tomography (pQCT) .............. 11 1.12.3 High resolution pQCT (HR-pQCT) ............................................. 12 2 AIM ........................................................................................................... 13 3 MATERIALS AND METHODS.............................................................. 14 3.1 Subjects ............................................................................................... 14 3.2 Anthropometrics and questionnaires ................................................... 14 3.3 Estimation of age at peak height velocity (PHV) ................................ 14 3.4 X-ray registers ..................................................................................... 15 3.5 Measurements of bone density ............................................................ 15 3.6 Ethical considerations ......................................................................... 17 3.7 Statistics .............................................................................................. 17 4 RESULTS AND DISCUSSION ............................................................... 19 ii
4.1 Paper I .................................................................................................. 19 4.1.1 Main results ................................................................................. 19 4.1.2 Conclusion ................................................................................... 20 4.1.3 Discussion .................................................................................... 20 4.2 Paper II ................................................................................................ 22 4.2.1 Main results ................................................................................. 22 4.2.2 Conclusion ................................................................................... 23 4.2.3 Discussion .................................................................................... 23 4.3 Paper III ............................................................................................... 25 4.3.1 Main results ................................................................................. 25 4.3.2 Conclusion ................................................................................... 26 4.3.3 Discussion .................................................................................... 27 4.4 Paper IV ............................................................................................... 28 4.4.1 Main results ................................................................................. 28 4.4.2 Conclusion ................................................................................... 29 4.4.3 Discussion .................................................................................... 29 4.5 General discussion ............................................................................... 30 5 CONCLUSION ............................................................................................. 33 RELATED PUBLICATIONS NOT INCLUDED IN THE THESIS ............................... 34 ACKNOWLEDGEMENTS .................................................................................. 35 REFERENCES .................................................................................................. 36 iii
ABBREVIATIONS
aBMD
Areal bone mineral density
BMC
Bone mineral content
BMD
Bone mineral density
BTM
Bone turnover marker
CSA
Cross sectional area
DXA
Dual energy X-ray absorptiometry
EC
Endosteal circumference
GOOD
Gothenburg Osteoporosis and Obesity Determinants
HR-pQCT
High resolution pQCT
NTX
N-terminal telopeptide of type 1 collagen
OC
Osteocalcin
PBM
Peak bone mass
PC
Periosteal circumference
PHV
Peak height velocity
pQCT
Peripheral quantitative computed tomography
RCT
Randomised controlled trial
SD
Standard deviation
µSV
Microsievert
vBMD
Volumetric bone mineral density
WHO
World health organization
iv
DEFINITIONS IN SHORT
Bone turnover markers
Substances that reflect bone formation or bone
resorption and can be measured in samples of
blood or urine
Osteoporosis
A disease characterized by low bone density
and microarchitectural deterioration of bone
tissue, which leads to bone fragility and
increased risk of fracture
Peak bone mass
The maximal attained bone mass in life
Peak height velocity
The most rapid longitudinal growth
v
Anna Darelid
1 INTRODUCTION
1.1 The skeleton and its functions
The human skeleton consists of over 200 bones, arranged in a sophisticated
manner in order to protect vital organs and to allow movement of the body.
The axial skeleton (skull, vertebrae, rib cage) forms a protective shell around
the brain, spinal cord and inner organs, while the appendicular skeleton (the
upper and lower limbs) is crucial for motion. Bones serve as attachment sites
for muscles and ligaments, thereby enabling the body to move. The skeleton
is also a reservoir for minerals such as calcium and phosphate, harbors
hematopoiesis, and is an endocrine organ producing substances such as
osteocalcin, which influence both bone cells and other cells.
1.2 Bone structure
The skeleton is comprised of long (tubular) bones, such as humerus, radius,
femur and tibia, and flat bones, such as the skull, sternum, scapula and ileum
(1). Bones have a dense outer shell, called cortex, which is composed of
compact bone called cortical bone. Cortical bone constitutes 75-80% of the
skeleton and is found in the shafts of long bones, and on the surface of all
bones (2). It is composed of lamellae, concentrically arranged around a small
central canal with a blood vessel, forming a Haversian system (also called
osteon) (2). Inside the vertebrae and the epiphyses of the long bones,
trabecular bone is found. Trabecular bone is a rigid meshwork of mineralized
bone, where number, size and distribution of the trabeculae are arranged in
order to optimize strength. It constitutes 20% of the total skeletal mass, but
contributes with 65-70% of the total bone surface and is the most
metabolically active part of the skeleton, acting as a calcium reservoir (2).
Trabecular bone is superior in withstanding compressive stress, and therefore
is the predominant bone in the vertebrae (1). At different sites in the skeleton,
the proportion of cortical and trabecular bone vary. The distal forearm and
femoral neck constitute 25% trabecular and 75% cortical bone, whereas the
vertebraes contain more than two thirds trabecular bone (2). Loss of cortical
bone and loss of trabecular bone hence predispose to fractures at different
locations.
1
Bone density, bone geometry and bone development in young men
./0/12303)
!"#$%&'(#")$*+%)
4%5#/12303)
,*"-&#()$*+%)
,*"-&#(
60#/12303)
.+7*35%#()3'"8#&%)
9%"0*35%#(
9%"0*35%#()3'"8#&%)
Figure 1. Schematic view of a longitudinal section through the tibia, a long (tubular)
bone.
1.3 The bone cells
The skeleton consists of three different kinds of bone cells and of
extracellular matrix (ECM). 90% of the total bone volume is ECM, which
comprises mineralized matrix, organic matrix, lipids and water (3).
Hydroxyapatite, (Ca10 (PO4)6 (OH)2)2 is the main component of the
mineralized matrix and provides the majority of bone strength and stiffness.
The mineralized matrix accounts for 99% of the body’s storage of calcium
and 85% of the phosphorous (3). The organic matrix contains mainly type 1
collagen, as well as proteoglycans, growth factors, and glycoproteins. The
organic matrix is secreted by osteoblasts and is mineralized within 10-15
days (3).
Osteoblasts
Osteoblasts are responsible for bone formation. They originate from
mesenchymal stem cells in the bone marrow, and account for 4-6 % of the
bone cells (4). Osteoblasts build bone by secreting bone proteins and collagen
that form the bone matrix. Alongside collagen type 1, osteoblasts also
2
Anna Darelid
produce osteocalcin (OC), osteonectin, osteopontin and bone sialoprotein (4).
The average lifespan of an osteoblast is three months (5). The aging
osteoblast face three possible destinies: undergo apoptosis, become
embedded in the bone as an osteocyte, or transform into a bone lining cell
(6). The lining cells are flat cells located on top of a thin layer of
unmineralized collagen matrix which covers the bone surface. When bone
remodeling should not occur, they prevent direct interaction between
osteoclasts and bone matrix (4). In order to allow osteoclasts to attach to the
bone, the collagen matrix must be removed through collagenase secretion,
and possibly the lining cells are responsible for this (5).
Osteocytes
When bone is formed, some osteoblasts become entrapped in the newly
formed bone matrix and develop into osteocytes. Osteocytes account for
approximately 95% of the bone cells, they are long-lived and do not divide
(4). The osteocytes are located in lacunae and form a network via dendritic
extensions into canaliculi, which are fluid-filled channels where the cells
connect to each other. The osteocytes have the capacity to detect mechanical
pressure and load (6), and thereafter regulate bone remodeling by acting on
osteoblast and osteoclast differentiation and function (4).
Osteoclasts
Osteoclasts are the only cells that can resorb bone (7). They are essential for
physiological bone resorption during growth, for remodeling, and for
maintaining calcium homeostasis (8). Osteoclasts originate from
haematopoietic stem cells, and are formed by fusion of several
mononucleated cells resulting in large multinucleated cells (9). Osteoclast
differentiation is promoted by the interaction between receptor activator of
nuclear factor κB (RANK) ligand, a cytokine expressed by osteoblasts, and
RANK, expressed on osteoclasts (2). Mature osteoclasts can attach to the
bone surface, creating an acidic microenvironment that enables bone
resorption (10). After they have finished resorbing bone, osteoclasts undergo
apoptosis (2).
1.4 Bone remodeling
Bone remodeling is the constantly ongoing process where bone is resorbed
and formed (11). Just as roads, bridges and buildings, bone develop fatigue
damage (12). Bone has the unique ability to detect micro-cracks or apoptotic
osteocytes, remove the damaged bone, and replace it with new bone (13). The
osteocytes are the cells that sense microcracks and mehanical strain and
trigger bone remodeling (14). The remodeling cycle begins with recruitment
3
Bone density, bone geometry and bone development in young men
of osteoclasts for bone resorption and ends with bone formation by the
osteoblasts, with bone formation lasting approximately three times as long as
bone resorption (9). This process is completed in approximately 3-6 months
(1), and takes place in a basic multicellular unit (BMU), consisting of bone
resorbing osteoclasts, bone forming osteoblasts, osteocytes embedded in bone
matrix, lining cells and the capillary blood supply (9). Bone remodeling takes
place throughout the entire skeleton, and it has been estimated that the adult
skeleton is completely regenerated in 10 years (estimated turnover 10% per
year for the entire skeleton, considering cortical bone turnover on average 4%
and trabecular bone turnover on average 28% per year) (5). At the cellular
level, bone loss occurs because of an imbalance between osteoblast and
osteoclast activity. For example, oestrogen deficiency after menopause leads
to enhanced formation of osteoclasts, which causes increased bone turnover
and progressive loss of trabecular bone (15). Remodeling imbalance causes
reduced bone strength and can lead to osteoporosis (16).
1.5 Osteoporosis and its consequences
Osteoporosis is characterized by low bone density and microarchitectural
deterioration of bone tissue, leading to an increased risk of fracture (17). The
incidence increases with age, and at the age of 50, the remaining lifetime
probability for a fragility fracture in Sweden is around 20% for men and 50%
for women (18). The most common osteoporotic fractures are fractures of the
vertebrae (spine), proximal femur (hip) and distal forearm (wrist) (19).
Osteoporosis and its related fractures are a major public health issue. Patients
with fractures (especially hip fractures but also vertebral fractures) suffer loss
of quality of life and mobility, long-term disability and loss of independence
(20). Only half of those ambulatory before a hip fracture are able to walk
independently afterwards (21). Fractures also increase the mortality and
impose a financial burden on the health care system (20). In men,
osteoporotic fractures occur approximately 5-10 years later in life than in
women, and after a hip fracture morbidity and mortality rates are higher
among men (22). Osteoporosis is defined as bone mineral density (BMD) 2.5
standard deviations (SD) or more below the average of healthy young adult
women (23). Low BMD is a major risk factor for osteoporotic fracture (24).
Every SD decrease in BMD is associated with approximately a two-fold
increase in the age-adjusted hip fracture risk in postmenopausal women, and
with a three-fold risk increase in elderly men (24-26). Other important risk
factors for osteoporotic fracture are increasing age, female sex, previous
fracture, a family history of fracture, and systemic glucocorticoid treatment
(27-29). Additional risk factors are smoking, excessive alcohol intake and
4
Anna Darelid
low body mass index (BMI), as well as increased risk of falling related to
visual impairment, treatment with sedatives or reduced mobility (30-33). A
few years ago, FRAX®, a fracture risk assessment tool developed by the
WHO, was introduced as a mean to identify patients with high fracture risk.
It is a country-specific computer-based algorithm available on the internet,
which calculates fracture probability based on risk factors and patient
characteristics, with or without available measurements of femoral neck areal
BMD (aBMD) (34).
1.6 Bone mineral accrual during growth
From early childhood to late adolescence, there is an ongoing accumulation
of skeletal mass, which increases from approximately 70-95 g at birth to
2400 to 3300 g in young women and men, respectively (35). Skeletal growth
requires adequate production of growth hormone, thyroid hormones, growth
factors and sex steroids (36). Before puberty, skeletal growth is largely driven
by growth hormone. Sex steroids are responsible for epiphyseal maturation
and mineral accrual during adolescence (36). During childhood and
adolescence, longitudinal growth as well as changes in skeletal size and
shape occur (37). Bones become longer through endochondral ossification at
the growth plates, and wider by periosteal apposition. During puberty, bone
formation also occurs at the endosteal, inner surface of the cortical bone (37).
Skeletal modeling during growth differs from bone remodeling, since it leads
to new bone formation at a different location than the site of resorption,
resulting in alterations in bone shape and net accrual of bone tissue (38).
Before puberty, no substantial sex difference has been reported in bone mass
of the lumbar spine, femur and radius, after adjustment for age, physical
activity and nutrition (39). During puberty, bone size increases while
volumetric BMD (vBMD) remains almost constant in both sexes (40). At the
end of puberty, males have higher BMD, mainly due to greater bone size in
males compared to females (37). In males, the prolonged bone maturation
period results in larger increases in cortical thickness and bone size. Cortical
thickness increases more by periosteal apposition of bone in males, resulting
in a stronger bone, whereas in females more bone is deposited at the
endosteal, inner surface (39). There is no significant sex difference in vBMD
at the end of puberty (40, 41). A large part of the bone mineral content
(BMC) accrual takes place during the period of adolescent growth
surrounding peak height velocity (PHV), which is the time of the most rapid
longitudinal growth. Depending on skeletal site, 33% to 46% of the adult
BMC has been reported to be accrued in the circumpubertal years (-2 to +2
5
Bone density, bone geometry and bone development in young men
years from PHV) (42). Thus, this period of life is of great importance in order
to optimize peak bone mass.
1.7 Peak bone mass
During childhood and adolescence, bone mass increases until a plateau is
reached, the peak bone mass (PBM) (43). The timing of PBM has been
debated, and differs between the sexes, between different skeletal sites, and
also between different measurement methods (44-50), but PBM is generally
believed to be reached in the late teenage years or young adult years (42).
Achieving a high PBM is considered a key determinant of skeletal health
throughout life. The bone mass of an individual later in life is a result of the
peak bone mass accrued, as well as the subsequent rate of bone loss (15). It
has been proposed that an increase in PBM of 10% (about 1 SD) could delay
the onset of osteoporosis by 13 years, and could reduce the risk of fracture by
50% in postmenopausal women (37). Maximizing peak bone mass therefore
seems to be of great importance in order to reduce the risk of osteoporotic
fractures.
1.8 Determinants of peak bone mass
Heredity is the major determinant of PBM, and approximately 60-80% of the
variance in PBM has been attributed to genetic factors (36, 51). Several
environmental factors also influence PBM, among them nutritional intake,
physical activity and smoking. Key nutritional factors are adequate intake of
calcium and vitamin D. Association studies between calcium intake and
BMC or BMD have been performed in children and adolescents, and most,
but not all, suggest a positive association (52, 53). Several prospective
randomized controlled trials with calcium supplemention have also
demonstrated a positive effect on aBMD (53). However, in a review and
meta-analysis of 19 studies, authors concluded that calcium supplementation
in healthy children had no effect on aBMD at the hip or spine, but a small
positive effect was seen on aBMD of the upper limb (54, 55). Few of the
studies incuded in the review were performed in children with low baseline
calcium intake. In another meta-analysis, authors concluded that increased
dietary calcium intake significantly increased total body and lumbar spine
BMC in children with low baseline calcium intake (56). Vitamin D is
essential to bone mineralization because of its effects on intestinal calcium
absorption and on bone mineral accrual (57). Vitamin D levels in the body
are influenced by dietary intake, genetic factors, and endogenous synthesis in
the skin following sunlight exposure, more specifically ultraviolet B (UVB)
6
Anna Darelid
irradiation (58, 59). In the northern hemisphere at latitudes greater than 40°N
(north of Madrid), the sunlight is not strong enough to trigger vitamin D
synthesis in the skin from October to March (59). In a review and metaanalysis of 6 studies, the authors concluded that it is unlikely that vitamin D
supplements are beneficial for bone health in children and adolescents with
normal vitamin D levels, but supplementation in deficient children and
adolescents could result in clinically important improvements in bone density
(60, 61). Insufficient serum vitamin D (25(OH)D) levels were recently
demonstrated to be associated with low aBMD in Finnish children and
adolescents age 7-19 years (62). In the Finnish study, only 29% of the 195
subjects had sufficient (>50 nmol/l) vitamin D status over the school year
(62). The authors concluded that the findings may be representative of other
Nordic and North European countries. Physical activity seems to be a key
factor to increase bone mineral accrual during childhood and adolescence.
The skeleton adapts to the forces and loads it experiences by increasing bone
mass and remodeling in order to increase strength (63). Weight-bearing
activities, ideally involving jumping, turning and sprinting, are preferred over
non weight-bearing activities such as swimming or bicycling when it comes
to increasing bone mass (64, 65). In children before and during puberty,
positive effects of weight-bearing exercise on bone have been demonstrated
in exercise intervention trials (63, 66-68). Recently, larger gains in BMD but
no increased fracture risk was reported in a study of schoolchildren in
Malmö, Sweden, taking part in daily physical education during six years
compared to controls (200 min versus 60 min physical education weekly)
(69). The authors concluded that a daily physical activity program ought to be
implemented from school start for all children. Cross-sectional and
longitudinal observational studies suggest that the beneficial effects of
physical activity on bone persist into young adulthood (70-72). In the GOOD
study, men who increased their physical activity between baseline (18-20 yrs)
and follow-up (23-25 yrs) had an advantageous development of aBMD,
trabecular vBMD, and cortical bone size (73), indicating that also in young
adulthood, physical activity has a positive effect on bone development.
Another lifestyle factor potentially influencing peak bone mass is smoking.
Smoking has been associated with reduced bone mass and increased fracture
risk in adult men and women (30, 74-76). Less is known about the effect of
smoking at the time of peak bone mass accrual, but studies have
demonstrated a negative relationship between smoking and BMD in both
male and female adolescents (77-79). In the GOOD cohort, cross-sectional
data showed that smoking was associated with lower aBMD of especially the
femoral neck, and reduced cortical thickness of the radius and tibia at age 1820 years (80), and longitudinal data demonstrated that smoking was
associated with impaired bone mass development in young adulthood (81).
7
Bone density, bone geometry and bone development in young men
1.9 Pubertal timing and peak bone mass
Another variable suggested to influence peak bone mass is pubertal timing
(39). Late menarche has been associated with low aBMD and compromised
microstructure of the radius and tibia in young adult women (124 women,
20.4±0.6 years (mean±SD)) (82, 83). Areal BMD at all sites was
demonstrated to be inversely related to pubertal timing in teenagers of both
genders, in a healthy cohort with variations in pubertal timing within the
normal range (78 girls and 85 boys, 15.1±1.0 and 16.2±0.9 yrs at follow-up,
respectively) (84). Results from another study showed lower BMC in late
maturing males and females at 13-15 years of age, however, in late
adolescence and young adulthood (17-28 years of age), no significant
differences in BMC in early, middle, and late maturing men were seen, while
late maturing females developed less bone mass throughout adolescence than
their early and average maturing peers (85). In the GOOD study, pubertal
timing in relation to BMD and bone size was investigated cross-sectionally
(642 men, 18.9±0.5 years), demonstrating that late pubertal timing was
associated with lower aBMD at all measured sites, lower cortical and
trabecular vBMD in both the radius and tibia, as well as reduced cortical
thickness of the radius and tibia (86). In order to establish whether these
deficits remain in adulthood, longitudinal studies are needed.
1.10 Fractures during growth
More than one in three children suffers a fracture during growth (87, 88), and
boys have a higher risk than girls of sustaining a fracture in the first 16 years
of life (89). It has been established that low aBMD is associated with
prevalent fractures in children as well as in adults (90-94), and it has been
suggested that fractures during childhood could be a predictor of low peak
bone mass and persistent bone fragility (95). A recently published 27-year
prospective longitudinal study demonstrated that in men, a childhood fracture
was associated with low BMD and smaller bone size in adulthood (age 30-44
years), while in women, the deficit did not reach statistical significance (96).
In contrast to this finding, there was no association between a self-recalled
childhood fracture and future fractures in a large cohort study (97). The peak
incidence of fractures is at the age of 11 to 12 years among girls and 13 to 14
years among boys (88, 90, 98, 99), which coincides with the age at peak
height velocity, but fracture incidence has not previously been investigated
directly in relation to PHV. Studies have demonstrated that age at PHV
preceeds the peak in bone mass accrual by approximately one year (100,
101). The delay in bone mass accrual in relation to linear growth has been
suggested to cause a transient skeletal deficit in bone mass and
8
Anna Darelid
mineralization, increasing the susceptibility to fractures at this period in life
(95, 102). Previous studies have mainly used dual energy X-ray
absorptiometry (DXA) technique when assessing bone mass in relation to
fractures in children and adolescents, and consequently it has not been
clarified whether it is deficits in bone density or bone size that is the main
contributor to fractures during growth.
1.11 Bone turnover markers
In recent years, attention has been drawn to the use of bone turnover markers
(BTM) in the evaluation of osteoporosis treatment (103-106), and also as a
determinant of fracture risk (107-109). Bone turnover markers are substances
that reflect bone turnover and can be measured in samples of blood or urine.
They can be divided into two categories: bone formation markers, which
reflect osteoblast activity, and are byproducts of collagen synthesis, matrix
proteins or osteoblastic enzymes; and bone resorption markers, which reflect
osteoclast activity and are mainly degradation products of type 1 collagen
(38). A common bone formation marker is osteocalcin (OC), produced by
osteoblasts during osteoid synthesis (110). It is incorporated directly into
bone matrix, but some newly synthesized and secreted OC circulates in blood
(111). One of the bone resorption markers used is N-terminal telopeptide
fragment (NTX), a collagen degradation fragment which, when bone is
resorbed, is released into the blood and subsequently excreted in urine (112).
It can be measured in serum (sNTX) or urine (uNTX). Several other markers
of bone turnover are available. Bone turnover during growth can roughly be
divided into four periods: infancy, prepubertal period, puberty and the
postpubertal period, with corresponding changes in the levels of BTM (111).
During puberty, levels of bone turnover markers increase, and have been
demonstrated to be higher in early puberty and midpuberty compared to
advanced puberty (113-115). If measurement of bone turnover markers can
predict bone development around the time of peak bone mass has not
previously been investigated, but is one of the foci of the present thesis.
9
Bone density, bone geometry and bone development in young men
1.12 Techniques for measuring bone
density
1.12.1 Dual energy X-ray absorptiometry (DXA)
The DXA scanner was introduced in the late 1980s, and is the most widely
used technique to assess bone density. In order to separate dense tissue from
soft tissue, the DXA scanner produces txo X-ray beams, one with high
energy and one with low energy. For each beam, the amount of X-ray that
passes through the body is measured, and bone density can be calculated. The
radiation dose from a DXA examination is very low, ranging from 1-10 µSv
for a spine and hip examination, which is comparable to the daily natural
background radiation (116). The procedure is painless and noninvasive. In
clinical use, DXA is primarily used to measure BMD of the lumbar spine and
femoral neck. These measurements are used to diagnose osteoporosis, assess
fracture risk, or monitor response to treatment. In postmenopausal women,
the interpretation of the results are made in comparison to T-scores. A Tscore equal to or less than -2.5 means that the BMD value lies 2.5 SDs or
more below the average value in young adult women, and indicates
osteoporosis according to the WHO classification of osteoporosis from 1994
(117). In younger individuals, Z-score is used instead of T-score. The Z-score
represents the number of SDs that a given value for BMD deviates from the
average value for the respective age and gender (118). Limitations with the
DXA technique include that it renders two-dimensional projection images.
The BMC of a given area is measured, and BMD (aBMD) is calculated by
dividing BMC with area (g/cm2). Thus, no consideration is given to the depth
or volume of the bone, which means that a smaller bone can be falsely
interpreted as having a low BMD. This is particularly a problem when
measuring children (116). Measurement errors also occur because of the
heterogeneity in soft tissue composition in different persons (accuracy error).
The precision errors are smaller than the accuracy errors because when a
person is rescanned, the effect of adipose tissue on the measurement is the
same. Results and radiation dose can differ somewhat when using DXA
scanners from different manufacturers (116).
10
Anna Darelid
!
!
!
Figure 2. Images assessed by DXA (Hologic Discovery W). A) Total body B) Total
hip C) Lumbar spine.
1.12.2 Peripheral quantitative computed
tomography (pQCT)
Computed tomography is an X-ray based technique that provides threedimensional information on morphology and composition of the scanned
area. The peripheral quantitative computed tomography (pQCT) is a QCT
device designed to measure peripheral bones, typically the distal forearm
(radius) and the distal tibia (119). The radiation dose is low, less than 3 µSv
for a single slice and increases in a multiple-slice protocol (120, 121). Unlike
DXA, the pQCT renders cross-sectional images. This enables the separation
of cortical and trabecular bone, so that vBMD of the cortical and trabecular
bone compartments can be determined separately. It also allows for
investigation of the geometrical bone properties. Information about trabecular
bone traits are obtained through a scan at 4% of the bone length in the distal
direction of the proximal end of the bone, while information about cortical
bone traits is obtained through a scan at 15-65% of the bone length in the
distal direction of the proximal end of the bone. Apart from vBMD of the
trabecular and cortical bone, cortical thickness, cortical CSA, endosteal and
periostal circumference can be obtained, which enables us to study size and
density of the bone separately.
11
Bone density, bone geometry and bone development in young men
1.12.3 High resolution pQCT (HR-pQCT)
Recently, a multislice high-resolution pQCT has come into use. A HR-pQCT
is a pQCT device that performs several cross-sectional slices and produces a
three-dimensional image of the bone. The resolution is high (slice thickness
82 µm) and enables investigation of the microstructure of the trabecular bone:
the number of trabeculae, trabecular thickness, and how far separated the
trabeculae are.
12
Anna Darelid
2 AIM
The general aim of the thesis was to study the development of bone density
and bone geometry in young men around the time of peak bone mass, and to
evaluate the association between pubertal timing and bone development in
this period of life. In addition, the aim was to investigate whether bone
turnover markers could predict bone development in young men, and also to
establish if fracture during childhood and adolescence was related to bone
density and bone geometry in young adulthood.
The specific aims of the papers included in the thesis were:
I.
To determine if it is the bone size or the vBMD that is most
strongly associated with X-ray-verified prevalent fractures
during childhood and adolescence in young men.
II.
To investigate the site-specific development of bone
geometry, aBMD, and vBMD in young men during a fiveyear follow-up period, between the age of 19 and 24 years.
III.
To establish if pubertal timing is related to the development
of bone geometry, BMC, aBMD, and vBMD in young men
between the age of 19 and 24 years, and also to determine if
late puberty is associated with remaining low bone mass in
young adulthood in men.
IV.
To evaluate if baseline measurements of OC and NTX could
predict the development of bone geometry, BMC, aBMD,
and vBMD in young men between the age of 19 and 24
years.
13
Bone density, bone geometry and bone development in young men
3 MATERIALS AND METHODS
3.1 Subjects
All papers included in the thesis are based on the Gothenburg Obesity and
Osteoporosis Determinants (GOOD) Study. The GOOD study is a
population-based study with the aim to determine both environmental and
genetic factors involved in the regulation of bone mass and fat mass. After
being randomly identified using national population registers, subjects were
contacted by telephone and asked to participate in the study. In order to be
included in the GOOD study, subjects had to be between 18 and 20 years of
age and willing to participate in the study. No other exclusion criteria were
used. 48.6% of the contacted men agreed to participate and were included in
the study. In total, 1068 men, 18.9±0.9 years of age, from the greater
Gothenburg area were included. The GOOD cohort was found representative
of the general young male population in Gothenburg (48). Five years after the
baseline visit, the men were contacted by letter and telephone and asked to
participate in the follow-up study. 112 men could not be reached, and 107
men declined to participate, leaving 833 men included in the five-year
follow-up study.
3.2 Anthropometrics and questionnaires
Height was measured with a wall-mounted stadiometer, and weight was
measured to the nearest 0.1 kg. A self-administered questionnaire was used
both at baseline and follow-up to collect information about nutritional intake,
fracture history, and physical activity pattern. Calcium intake was calculated
from reported dairy consumption. Blood samples were drawn and stored at
-80°C until analysis.
3.3 Estimation of age at peak height
velocity (PHV)
Out of the 1068 subjects included in the GOOD study, complete growth
charts were available for 642 subjects. Age and BMI did not differ between
the subset with available growth charts and the complete cohort, indicating
that the subset is representative for the complete GOOD cohort (86). Growth
charts were used for determination of age at peak height velocity according to
the infancy-childhood-puberty (ICP) model. The ICP model isolates three
distinct components of growth (infancy, childhood, and puberty) that can be
14
Anna Darelid
described using three different mathematical functions (122, 123). Age at
PHV was defined as the age at maximum growth velocity during puberty,
and was estimated by the algorithm. Age at PHV is the most common
indicator of maturity used in longitudinal studies (85), and is generally
believed to be reached within 2 years of pubertal onset (123, 124).
3.4 X-ray registers
In order to verify reported fractures, X-ray registers were searched. We
searched the centralized computerized X-ray registers containing radiographs
and reports from radiologists from 1991 onwards from the public hospitals in
Gothenburg (Sahlgrenska, Mölndal and Östra (including Queen Silvia’s
children’s hospital)). Computerized registers were also searched in the small
private hospitals (Carlanderska and Lundby). A central archive containing Xray reports from the entire Västra Götalandsregionen (a region encompassing
a large part of southwestern Sweden with approximately 1.5 million
inhabitants) of earlier dates was searched manually using social security
numbers, as was the local archive of the Queen Silvia’s children’s hospital in
Gothenburg. The fractures were classified according to skeletal site, based on
the radiologist’s report. No information concerning trauma severity was
available. Subjects reporting fractures that could not be verified in the records
were excluded from analysis.
3.5 Measurements of bone density
At both the baseline and the follow-up visit, the subjects underwent
measurements with DXA and pQCT. At the follow-up visit, subjects also
underwent examination with HR-pQCT (results not presented in this thesis).
Dual energy X-ray absorptiometry (DXA)
BMC (g), bone area (cm2), and aBMD (g/cm2) of the total body, femoral neck
and total hip (of the left leg), and the left and right radius were assessed at
baseline and follow-up using the Lunar Prodigy DXA (GE Lunar Corp.
Madison, WI, USA). The Lunar Prodigy DXA used at the follow-up visit was
not the same specimen used at the baseline visit. A cross-calibration between
the two Lunar Prodigy DXA machines was performed at the time of followup and is described in detail in paper II. One person performed all the
measurements of the baseline study, and another person performed all the
measurements of the follow-up study. The CVs for the aBMD measurements
ranged from 0.5-3%, depending on application.
15
Bone density, bone geometry and bone development in young men
Peripheral quantitative computed tomography (pQCT)
A pQCT device (XCT-2000; Stratec Medizintechnik, GmbH, Pforzheim,
Germany) was used to scan the distal arm (radius) and the distal leg (tibia) of
the nondominant arm and leg, respectively. A 2-mm-thick tomographic slice
was scanned with a voxel size of 0.50 mm. The cortical vBMD (not including
the bone marrow) (mg/cm3), cortical cross-sectional area (CSA; mm2),
endosteal circumference (EC; mm), periosteal circumference (PC; mm) were
measured using a scan through the disphysis (at 25% of the bone length in the
proximal direction of the distal end of the bone) of the radius and tibia. The
threshold for cortical bone was 711 mg/cm3. Polar strength strain index of the
cortex (SSI; mm3), was calculated by the software, version 6.00 of the XCT2000. SSI represents an estimation of the mechanical strength of the cortical
bone (125). Trabecular vBMD (mg/cm3) was measured using a scan through
the metaphysis (at 4% of the bone length in the proximal direction of the
distal end of the bone) of these bones. Trabecular vBMD was assessed using
the inner 45% of these bones. Tibial bone length was measured from the
medial malleolus to the medial condyle of the tibia, and length of the forearm
was defined as the distance from the olecranon to the ulna styloid process.
Measurements at the follow-up visit were made using the same procedure and
the same equipment as at the baseline visit. One person performed all the
measurements of the baseline study, and another person performed all the
measurements of the follow-up study. The CVs were less than 1% for all
pQCT measurements.
Figure 3. To the left, a scan through the metaphysis of the radius (and ulna) for
measuring trabecular vBMD. To the right, a scan through the diaphysis of the radius
(and ulna) for measuring cortical vBMD and cortical geometry. (XCT-2000; Stratec
Medizintechnik, GmbH, Pforzheim, Germany)
16
Anna Darelid
3.6 Ethical considerations
The ethical considerations concerning the GOOD study included radiation
exposure of study participants. Although DXA and pQCT are techniques
with very low radiation, there is a small additional exposure. In the follow-up
study, when participants were examined with DXA, pQCT and HR-pQCT,
the effective radiation dose was estimated to 0.2 mSv, which corresponds to
approximately 2 months of background radiation. At baseline, the dose was
even lower since only DXA and pQCT measurements were performed.
Venous blood sampling is an invasive procedure, but with minimal risks of
complications. There is also the question of personal integrity. The data was
collected in a database where personal data only existed in coded form, and
consequently no connection between particular individuals and data could be
made. Only authorized persons had access to the database. The results have
been presented on a group level, so that no individual can be identified.
Participants could withdraw from the study at any point. Written and oral
informed consent was obtained from all included subjects. The regional
ethical review board at the University of Gothenburg approved all studies
included in the thesis.
3.7 Statistics
Differences in anthropometric characteristics and bone parameters in paper I
(fracture/non-fracture) were investigated using an independent samples t-test,
in paper II (baseline/follow-up) using a paired-samples t-test, and in paper III
(early/middle/late puberty) and IV (quartiles of OC level) using one-way
ANOVA followed by Bonferroni post hoc test. Chi-square test was used in
all papers to compare categorical variables. To evaluate the association
between prevalent fracture and bone variables (paper I) and age at PHV
(paper III), binary logistic regression analysis was performed. Linear
regression equations including covariates height, weight, smoking, calcium
intake and physical activity were performed in order to calculate adjusted
baseline and 5-year bone variables and the 5-year changes (also adjusted for
follow-up time) in bone variables (paper II). To determine which variables
were independent predictors of the change over 5 years in different bone
variables, stepwise multiple linear regression analyses were performed (paper
III-IV). The stepwise selection process criterion for entry into the model was
a p-value ≤0.05, and the criterion for removal from the model was a p-value
≥0.10. The percentage of the variation (R2) of the change over five years in
each bone parameter explained by different variables was calculated using
the stepwise linear regression model (paper III-IV). Bivariate correlations
were calculated using Pearson’s correlation (paper II and IV). Parameters that
17
Bone density, bone geometry and bone development in young men
did not display a normal distribution were logarithmically transformed before
being entered into the regression analysis. In paper IV, a spline regression
model was used to study the linearity of the association between OC and
changes in BMD in more detail. A p value less than 0.05 was considered
significant. Data was analyzed using SPSS software for Windows (paper I,
version 16.0, paper II version 15.0 and 19.0, paper III version 19.0, paper IV
version 20.0).
Statistical methods used: Paper I Independent samples t-­‐test x Paired samples t-­‐
test x ANOVA and post hoc test x x Chi square test x x x x Binary logistic regression x x Linear regression x x x Bivariate correlation x x Log transformation x x x x x Spline regression model Paper II Paper III Table 1. The different statistical methods used in papers I-IV.
18
Paper IV Anna Darelid
4 RESULTS AND DISCUSSION
4.1 Paper I
Trabecular volumetric bone mineral density is associated with
previous fracture during childhood and adolescence in males:
the GOOD study
In the first study in the thesis, we investigated the association between
fracture during childhood and adolescence and aBMD, vBMD and bone
geometry in young adulthood. 304 men were identified as having had at least
one previous X-ray-verified fracture, while 687 men were non-fracture
subjects.
4.1.1 Main results
•
Men with prevalent fracture had
Ø lower aBMD than men without fracture at all measured sites
(total body, lumbar spine, total hip, radius).
Ø lower cortical and trabecular vBMD of the radius and tibia, as
well as slightly reduced cortical thickness of the radius due to a
larger endosteal circumference.
•
Trabecular vBMD of the radius was most strongly associated with
previous fracture (radius fracture as well as any fracture).
•
Among distal forearm fractures, fracture of the nondominant arm (mostly
the left arm) was clearly overrepresented.
•
Fracture incidence was shown to reach its peak at age at PHV, followed
by a sharp decline thereafter (fig 4).
19
Bone density, bone geometry and bone development in young men
Number of fractures
60
50
40
30
20
10
0
Timing of fractures in relation to PHV (years)
Figure 4. Fracture incidence according to PHV. Fracture incidence increased with
advancing age and reached its peak at the time of PHV, followed by a sharp decline
thereafter. From Darelid et al, JBMR (126). Reprinted with permission from the
publisher.
4.1.2 Conclusion
In conclusion, previous fracture was associated with lower aBMD at all
measured sites and lower vBMD, especially trabecular vBMD of the radius
and tibia.
4.1.3 Discussion
304 out of 991 men (30.7%) of the men had experienced a fracture during
growth, which corresponds to other reports of fracture incidence in males in
this age group (88). When we analyzed the distribution of forearm fractures,
we found that fracture of the nondominant arm (mostly the left arm) was
clearly overrepresented. In a previous study of the same cohort, aBMD was
demonstrated to be higher in the dominant arm than in the nondominant arm,
indicating that lower aBMD of the nondominant arm may have contributed to
this distribution (127). Fracture incidence was shown to reach its peak at age
at PHV, followed by a sharp decline thereafter (fig 4). Several earlier studies
have demonstrated a peak in fracture incidence of approximately 11-12 years
for girls and 13-14 years for boys (88, 98, 128), which coincides with age at
PHV. To the best of our knowledge, this is the first study ever to investigate
fracture incidence in direct relation to age at PHV. Our findings indicate that
20
Anna Darelid
the skeleton is most susceptible to fracture when longitudinal growth is at its
peak, which corresponds well to earlier findings that body size-corrected
aBMD decreases to its minimum during age at PHV (102). Our results
suggest that a reduction in trabecular vBMD, possibly in combination with
reduced cortical thickness, could be responsible for this reduction in aBMD
at the time of PHV. Taes and colleagues presented similar results in a study
of adult men (25-45 years), although in that study cortical thickness was
more strongly associated with childhood fracture than trabecular vBMD
(129). In younger boys (15.2±0.5 years (SD±mean) at follow up), Chevalley
et al demonstrated an association between fracture and lower femoral neck
aBMD and lower trabecular vBMD of the tibia, due to a reduction in
trabecular number as measured with HR-pQCT (130). The same authors
reported that fractures were associated with lower aBMD and lower
trabecular vBMD of the radius, as well as reduced trabecular thickness in
young adult women (20.4±0.6 years, mean±SD), findings in concordance
with the present study (131). Farr and colleagues concluded in a study of 465
girls 8-13 years old, that previous fracture was associated with lower
trabecular vBMD, but not bone size, of the femur and tibia (132). In the fiveyear follow-up of the GOOD study, Rudäng et al investigated the association
between childhood fractures and trabecular bone microstructure. Men with a
childhood fracture (fracture ≤16 years of age) had lower trabecular bone
volume fraction at both the radius and tibia, mainly due to smaller trabecular
thickness but also increased trabecular separation, and at the radius also
reduced trabecular number (133). The assumption that fractures in childhood
may predict low peak bone mass was recently supported in a 27-year
prospective study in men (96). In order to improve fracture risk prediction
and develop prevention strategies, increased knowledge about the etiology of
bone fragility is valuable.
21
Bone density, bone geometry and bone development in young men
4.2 Paper II
Cortical
consolidation
due
to
increased
mineralization and endosteal contraction in young
adult men: a five year longitudinal study
The second study was a longitudinal study investigating the normal
development of aBMD, vBMD and bone geometry in young adulthood in
men. Out of the 1068 men originally included in the GOOD study, 833 men
agreed to participate in the five-year follow-up study.
4.2.1 Main results
•
Areal BMD of the total body, lumbar spine and radius increased by 3.4%,
4.2% and 7.8%, respectively, over the five-year period.
•
Areal BMD of the total hip and femoral neck decreased by 1.9% and
3.6%, respectively.
•
Both cortical and trabecular vBMD of the radius increased, as well as
cortical thickness of the radius due to a decreased endosteal
circumference (fig 5). At the tibia, similar results were seen except for
trabecular vBMD which decreased slightly. There was a suggested
decrease in periosteal circumference of the tibia.
•
The men included in the follow-up study were substantially heavier and
slightly taller than at baseline five years earlier. Their reported calcium
intake and weekly amount of physical activity were reduced compared to
the baseline visit.
22
Anna Darelid
18-20 YEAR-OLD
23-25 YEAR-OLD
Figure 5. Increased mineralization and increased cortical thickness due to
diminished endosteal circumference in young men between age 18-20 and 23-25
years. From Ohlsson and Darelid et al, JCEM (134). Reprinted with permission from
the publisher.
4.2.2 Conclusion
In conclusion, aBMD decreased at the hip but increased at the spine and
radius, and the increment in the long bones was explained by increased
vBMD and increased cortical thickness due to endosteal contraction.
4.2.3 Discussion
Not many large, population-based longitudinal studies around the time of
peak bone mass in males have been performed. To the best of our knowledge,
the present study is the only one using pQCT, which enables us to elucidate
whether change in density or size of the long bones explains the changes in
aBMD during this period in life. In a cross-sectional analysis of the GOOD
cohort, Lorentzon et al demonstrated that age was not correlated to aBMD of
the lumbar spine, femoral neck and total body in men between 18-20 years,
results that suggested that PBM had been reached at these sites (48). Radius
aBMD was correlated to age, as was cortical thickness, EC and cortical
vBMD of the radius, suggesting ongoing mineralization and increase in bone
size in the long bones at 18-20 years of age (48). Results from the present
study show that peak bone mass had been reached in the hip region, since
aBMD already started to decrease in men between 19 and 24 years. In a
longitudinal study including 527 men (16-40 years old), authors concluded
that peak bone mass at the hip occurred between 19 and 21 years of age,
findings relatively consistent with the present study (135). Similar results,
with the peak in hip BMC observed at approximately 18.5 yrs (and for
23
Bone density, bone geometry and bone development in young men
femoral neck BMC 16.5 years) was reported by Baxter-Jones et al in a study
with a mixed longitudinal design (42). Yet earlier, at approximately 16 years,
was the estimated PBM of aBMD at the hip in a longitudinal study by
Bachrach et al (136). Nilsson et al demonstrated that a reduced level of
physical activity between baseline and follow-up was associated with greater
loss of hip aBMD in the GOOD cohort (73). We hypothesize that weightbearing bones are more dependent on continued physical activity in order to
minimize bone loss. Study participants in the GOOD cohort who started to
smoke between baseline and follow-up also lost more in total hip and femoral
neck aBMD (81). There was an increase of 4.2% in lumbar spine aBMD
between baseline and follow-up, suggesting that in the GOOD cohort, peak
bone mass was not reached before 18 years of age but between 18-25 years or
later. Lumbar spine PBM was reported to occur between 19-33 years of age
in the aforementioned study by Berger et al (135), and the peak in lumbar
spine BMC was at approximately 18.5 years in the study by Baxter-Jones et
al (42). In the cohort investigated by Bachrach et al, lumbar spine peak
aBMD was already reached by approximately 18 years (136). Also aBMD of
the radius continued to increase (on average 7.8%) between 19 and 24 years
in the GOOD cohort, and further investigation with pQCT elucidated that this
increase was due mainly to increased cortical vBMD and greater cortical
thickness as a result of reduced endosteal circumference. Thus, the process
suggested in the cross-sectional analysis of the GOOD cohort at 18-20 years
was confirmed, and continued until 23-25 years of age and possibly longer. A
longitudinal study including 88 males (22-39 years at baseline) demonstrated
increases in aBMD of the radius during a 4-year follow-up period (137), and
a Norwegian population-based longitudinal study using single X-ray
absorptiometry to investigate distal radius estimated peak bone mass in males
to 34 years (138). Those results support the conclusion that PBM has not yet
been reached at the radius in the GOOD cohort. In summary, peak bone mass
appears to be reached at the hip region already before or around 18 years of
age, followed by the spine in late teenage years or in the twenties, and in the
long bones well after that. In the vast majority of studies, females reach PBM
before males at all sites.
24
Anna Darelid
4.3 Paper III
Catch up in bone acquisition in young adult men
with late normal puberty
In the third study, we investigated longitudinal development of aBMD, BMC,
vBMD and bone geometry in relation to age at PHV. 501 men with available
data on age at PHV participated in the baseline and follow-up study and were
included in this study. We knew from previous results that men with late (but
within the normal range) puberty had lower aBMD at age 18-20 years. The
cohort was divided into tertiles according to age at PHV. Our aim was to
determine if this deficit persisted into early adulthood, and to investigate
whether pubertal timing influenced bone development in young adulthood.
4.3.1 Main results
•
Men with late puberty
Ø had significantly larger increases in aBMD and BMC of the total
body, lumbar spine and radius than men with early puberty.
Ø lost less in femoral neck aBMD.
Ø gained significantly more in cortical and trabecular vBMD of the
radius, as well as in cortical CSA and PC of the radius.
•
Age at PHV was an independent positive predictor of
Ø the increase in aBMD and BMC of the total body, lumbar spine
and radius (fig 6).
Ø the increase in trabecular and cortical vBMD of the radius.
Ø the increase in cortical CSA and thickness of the radius.
25
Bone density, bone geometry and bone development in young men
At age 23-25, no significant differences were seen between men in the
different pubertal groups at the measured bone sites except for radius
aBMD, which was still lower in men with late puberty due to lower
cortical and trabecular vBMD.
Change in radius aBMD (g/cm2)
•
0.20
Observed
R2=23.5%
Linear
0.15
0.10
0.05
0
-0.05
12
14
16
Age at peak height velocity (years)
Figure 6. Age at PHV predicts increase in radius aBMD between 19 and 24 years.
Higher age at PHV is associated with a larger increase in radius aBMD between 19
and 24 years of age. From Darelid et al, JBMR (139). Reprinted with permission
from the publisher.
4.3.2 Conclusion
In conclusion, our results demonstrate that late puberty within the normal
range was associated with a substantial catch up in aBMD, BMC, vBMD and
bone size in young adulthood. No significant differences in aBMD or BMC
of the lumbar spine, femoral neck or total body were seen at age 24 in men
with late puberty, whereas aBMD of the radius was still significantly lower in
men with late pubertal onset, due to lower cortical vBMD but not reduced
bone size.
26
Anna Darelid
4.3.3 Discussion
The relationship between pubertal onset and adult bone mineral density has
been mainly studied in women. Studies have shown that late menarche was
associated with low aBMD and higher fracture risk at several sites in
postmenopausal women (140-144), whereas early menarche was associated
with high aBMD in premenopausal women (145, 146). In more recent studies
by Chevalley and colleagues, an inverse relationship between aBMD of the
radius and femoral neck and menarcheal age in young women (20.4±0.6
years, mean±SD) and in premenopausal women (45.8±3.4 years, mean±SD)
was observed (82, 83). In the present study investigating changes between
18-20 and 23-25 years, no significant differences between men with early,
middle and late puberty in aBMD of the lumbar spine, total hip, femoral neck
and total body were seen at follow-up (23-25 yrs). Possibly, the effects of late
puberty on adult BMD and BMC differ in men and women. This assumption
is supported by the earlier mentioned study presented by Jackowski et al,
where no significant differences in BMC in early, middle, and late maturing
men were seen in late adolescence and young adulthood (17-28 years of age),
while late maturing females developed less bone mass throughout
adolescence than their early and average maturing peers (85). In the present
study, there were no significant differences in bone geometry at 23-25 years
of age, while cortical vBMD of the radius was significantly lower in men
with late puberty. In women, Chevalley et al demonstrated lower cortical
density and lower cortical thickness of the radius in young adult women with
late menarcheal age (83). Due to the longitudinal design of our study, we
could also investigate the relationship between pubertal timing and bone
development between 18-20 years and 23-25 years. In most bone variables,
men with late puberty had larger increases than men with early puberty, and
we concluded that there is a notable catch up effect in bone acquisition during
this period of life in men with late puberty. Nevertheless, the lower BMD
observed in teenagers with late puberty has clinical relevance, since this is a
period of high fracture incidence. In the present study, 43 out of 155 subjects
(27.7%) with early puberty had experienced at least one fracture during
growth or young adulthood, compared to 56 out of 147 (38.1%) men with
middle, and 62 out of 154 (40.3%) men with late puberty (p=0.049). We also
observed a 28% increased risk of having had a fracture during growth and
young adulthood for each year age at PHV increased. Chevalley et al
demonstrated even larger increases in the risk of having had a fracture with
increasing age at menarche in young women (131).
27
Bone density, bone geometry and bone development in young men
4.4 Paper IV
In the final study of the thesis, we investigated whether baseline
measurements of bone turnover markers could predict bone development in
young men between age 19 and 24 years. 817 men who took part in the
baseline and follow-up visit, and had a baseline value of osteocalcin and
NTX, were included in the present study. The men were divided into
quartiles according to level of OC.
4.4.1 Main results
•
Men with a high OC level at baseline
Ø had significantly larger increases in aBMD and BMC of the
lumbar spine compared to men with a low OC level at baseline.
Ø lost less in total hip aBMD and in trabecular vBMD of the tibia.
Ø gained significantly more in trabecular vBMD of the radius, as
well as in cortical CSA of the radius and tibia.
•
Osteocalcin was an independent positive predictor of the increase in
BMD and BMC of the total body, lumbar spine and radius.
•
A high OC level at the age of 19 predicted a favorable development in
BMC, aBMD (fig 7), vBMD and bone size between 19-24 years of age.
28
Anna Darelid
Figure 7. Change in lumbar spine aBMD between 19 and 24 years of age according
to level of OC at baseline. From Darelid et al, JCEM (147). Reprinted with
permission from the publisher.
4.4.2 Conclusion
In conclusion, our results demonstrate that high levels of OC at age 19 was
associated with larger increases in BMC, aBMD, vBMD and bone size in
young adulthood, indicating that measuring OC could be of value in the
evaluation of bone development in a young male.
4.4.3 Discussion
In this final study of the thesis, we demonstrated that OC, measured at
baseline, was an independent positive predictor of bone development in
young men between 19 and 24 years. In paper II, we reported increases in
aBMD of the lumbar spine, total body and radius, as well as decreased
aBMD of the femoral neck and total hip in this cohort (134), indicating that
this period in life is of importance in maximizing PBM. In paper III, age at
PHV was demonstrated to be a positive predictor of bone development
between 19 and 24 years in a subsample of men from the GOOD cohort
(139). Age at PHV is an objective measurement of pubertal timing, and has
been shown to be strongly correlated to age at menarche in females (148).
Data to calculate age at PHV are generally not available in the clinical
setting. When we divided the men into quartiles according to OC level at
baseline, we found that men with high (35.2±4.4 ng/ml, mean±SD) OC were
slightly younger and taller, weighed less, and had experienced age at PHV on
29
Bone density, bone geometry and bone development in young men
average one year later than men with low (17.7±2.3 ng/ml, mean±SD) OC at
baseline. In previous studies, markers of bone turnover have been
demonstrated to correlate well with age at PHV (149, 150). One small study
(n=100) reported a very close correlation between OC levels and the pubertal
growth spurt (151). We suggest that a young man with high OC at age 19 is
at a lower maturational level and therefore may increase more in bone
density, bone mass and bone size, than a man with low OC at this time in life.
The correlation coefficient for age at PHV and log OC was 0.38 (p<0.001),
indicating that measuring OC could provide some information about the age
at PHV and the bone maturational level. Longitudinal studies evaluating
levels of BTM in relation to bone development are scarce. One five-year
longitudinal study of 240 men (35-69 years) demonstrated that NTX,
measured at follow-up, was negatively correlated with the change in aBMD
at the femoral neck r=-0.21) and could explain 3.8% of the variance of the
change in femoral neck aBMD (152). In the present study, NTX was
positively correlated to change in femoral neck BMC (r=0.13) but not aBMD,
and could not explain any of the variance of the change in femoral neck BMC
or aBMD. OC, on the other hand, was positively correlated to the change in
femoral neck BMC and aBMD (r=0.18), and could explain 2.9% of the
variance of the change in femoral neck aBMD.
4.5 General discussion
The two main components influencing an individual’s risk of osteoporosis
are PBM, achieved by young adulthood, and the subsequent rate of bone loss
later in life (53). It has been proposed that osteoporosis should be considered
“a pediatric disease with geriatric consequences” (35). Although a large part
of the variation in PBM is genetically determined, it is also influenced by
environmental factors. Achieving optimal PBM requires adequate hormone
levels, proper nutrition (including sufficient intake of calcium and vitamin
D), and loading of the skeleton through weight-bearing physical activity. The
trend of increasing physical inactivity among contemporary youth is a
concern for overall health (153-155), including the acquisition of optimal
peak bone mass (156). Increased knowledge about the timing of PBM, as
well as factors that influence the acquisition of PBM, are valuable in order to
promote lifestyle choices that support the achievement of optimal PBM,
which could reduce the risk of osteoporosis later in life. In this thesis, we
present data from the GOOD study, a longitudinal study of young men
around the time of PBM. Our results suggest that PBM was reached in the
hip region in the late teens or early twenties, at the lumbar spine in the midtwenties, and in the long bones later than mid-twenties. Having had a fracture
30
Anna Darelid
during childhood or adolescence was associated with lower BMD, indicating
that a previous fracture is a risk factor for low BMD in young adulthood in
males. The peak incidence in fractures coincided with age at peak height
velocity, supporting the notion that this period in life confers a transient
skeletal fragility due to a discrepance in longitudinal growth and
mineralization. Men with late pubertal timing had lower BMD at 18-20 years
of age, but experienced larger gains in the following 5-year-period, resulting
in a catch up effect. At 23-25 years of age, there was still a deficit in radius
aBMD in men with late puberty, due to lower vBMD. We do not know if this
deficit will persist into old age, or if the men with late puberty will increase
further in vBMD of the long bones in the next few years. It appears as if late
puberty has more substantial consequences for BMD in women than in men,
but more studies are needed in order to clarify this. Possibly, the prolonged
growth period in boys compared to girls contributes to lessen the effect of
late puberty on PBM in males. We also showed that a high level of OC at age
18-20 was associated with larger gains in BMD and bone size in the
following five years. Possibly, measuring OC could be of help when
evaluating BMD in a young male, to get an indication of whether bone
density will continue to increase or if that process has ceased. Further studies
are needed in order to confirm this. A cross-sectional study performed within
the GOOD cohort showed that men involved in physical activity more than 4
hours/week had higher aBMD of the lumbar spine and femoral neck, higher
trabecular vBMD, and greater cortical thickness of the tibia, than men who
were sedentary (127). Subjects who started their present amount of physical
activity (minimum 4 hours/week) before age 13 had higher aBMD of the
femoral neck, cortical CSA of the tibia, and trabecular vBMD of the tibia,
than subjects who began at age 13 or later, suggesting that exercise before
and during puberty is important for the acquisition of peak bone mass (127).
When followed longitudinally, men in the GOOD cohort who increased their
physical activity between baseline and follow-up had larger increases in
aBMD of the lumbar spine and total body (73). They also had a small
increase in hip aBMD, while men who reduced their level of physical activity
had a decrease in hip aBMD (73). These results indicate that also in young
adulthood, physical activity is of importance to optimize peak bone mass. In
a cross-sectional analysis comparing smokers to non-smokers in the GOOD
cohort, smokers had lower aBMD of the total body, lumbar spine and femoral
neck, as well as reduced cortical thickness of the radius and tibia due to larger
endosteal circumference (80). Men who started to smoke between baseline
and follow-up gained less in aBMD of the total body and lumbar spine than
their nonsmoking peers (81). They also lost more in hip aBMD and in
trabecular vBMD of the tibia, indicating that smoking impairs bone
development in adolescence and young adulthood.
31
Bone density, bone geometry and bone development in young men
Osteoporosis is a major public health issue, and the burden both
economically and in terms of individual suffering will most likely increase in
the years to come. A growing number of people will be getting osteoporosis
due to increased longevity and a sedentary lifestyle. In children, adolescents
and young adults, we can promote the achievement of a high peak bone mass
by ensuring adequate calcium intake, supplementing vitamin D deficiency,
and encouraging a non-smoking lifestyle with daily physical activity, thereby
reducing the risk of osteoporosis and fractures later in life.
32
Anna Darelid
5 CONCLUSION
In a large cohort of young Swedish men investigated by DXA and pQCT, we
found that a previous fracture was associated with lower aBMD at age 19,
and especially with reduced trabecular vBMD of the radius. Between age 19
and 24 years, femoral neck aBMD decreased while lumbar spine aBMD
increased. Radius aBMD increased, due to increased cortical thickness and
continuing mineralization. Men with late puberty had larger gains in aBMD,
vBMD, and bone size, and lost less in aBMD of the femoral neck, reflecting
a catch-up in bone acquisition in young adulthood in men with late puberty.
A high level of OC at age 19 was associated with larger gains in aBMD,
vBMD, and bone size between 19 and 24 years of age. Even though the
majority of bone acquisition takes place in the circumpubertal years, this
thesis indicates that young adulthood is also a period of importance in order
to attain optimal PBM, which in turn could be crucial for the prevention of
osteoporosis and fragility fractures later in life.
33
Bone density, bone geometry and bone development in young men
RELATED PUBLICATIONS NOT
INCLUDED IN THE THESIS
Rudäng R, Darelid A, Nilsson M, Nilsson S, Mellström D, Ohlsson C,
Lorentzon M. Smoking is associated with impaired bone mass development
in young adult men: A 5-year longitudinal study. The Journal of Bone and
Mineral Research, October 2012;27(10):2189-2197.
Rudäng R, Darelid A, Nilsson M, Mellström D, Ohlsson C, Lorentzon M. Xray verified fractures are associated with finite element analysis derived bone
strength and trabecular microstructure in young adult men. The Journal of
Bone and Mineral Research, November 2013;28(10):2305-2316
34
ACKNOWLEDGEMENTS
Ett stort tack till Mattias Lorentzon, min handledare, som gav mig möjlighet
att prova på forskning och med entusiasm, stort kunnande och gott humör
guidat mig genom doktorandtiden.
Tack till Dan Mellström, min bihandledare, som bidragit med mångårig
erfarenhet inom osteoporosforskning.
Tack till alla medförfattare för värdefulla synpunkter och gott samarbete.
Tack alla på Enheten för geriatrik och CBAR för trevliga fikastunder,
givande diskussioner och ressällskap på kurser och konferenser.
Tack till Daniel Sundh, Martin Nilsson och Robert Rudäng för gott
kamratskap under åren som doktorand, tack till Anna Nilsson som svarat på
frågor om stort och smått under slutspurten, tack till Helena Johansson för
hjälp med statistiken och tack till Ulrika Hjertonsson som varit behjälplig
med allt som rör DXA:n.
Tack till alla studiedeltagare och alla som arbetat med GOOD-studien genom
åren.
Tack till tidigare och nuvarande chefer: Caterina Finizia som möjliggjorde
forskning under AT, Peter Gjertsson som uppmuntrade mig att söka forskarST och Björn Wall som gav mig utrymme i schemat att slutföra
avhandlingen.
Tack alla på Nuklearmedicin och Klinisk fysiologi för en väldigt trevlig
arbetsplats.
Tack Jenny, Kicki och Lisa för långa samtal och många skratt genom åren.
Tack hela kära familjen för hjälp med barnpassning och för stöd och
uppmuntran: mamma Monika, pappa Göran, Ann-Mari, Bengt, Johan, Maria,
Andreas, Einar, Isabell, Laura, Ylva, Mathias, Edgar, Flora, Bibbi, Johan,
Joakim, Martina och Emma.
Ett stort tack till Martin för all kärlek och till Joel, Elsa och Axel för att ni
finns.
35
Bone density, bone geometry and bone development in young men
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
Datta HK, Ng WF, Walker JA, Tuck SP, Varanasi SS 2008 The
cell biology of bone metabolism. Journal of clinical pathology
61:577-587
Woolf ADÅ, K. 2008 Osteoporosis - an atlas of investigation and
management. Oxford: Atlas Medical Publishing Ltd
Buck DW, 2nd, Dumanian GA 2012 Bone biology and physiology:
Part I. The fundamentals. Plastic and reconstructive surgery
129:1314-1320
Capulli M, Paone R, Rucci N 2014 Osteoblast and osteocyte: games
without frontiers. Archives of biochemistry and biophysics 561:3-12
Manolagas SC 2000 Birth and death of bone cells: basic regulatory
mechanisms and implications for the pathogenesis and treatment of
osteoporosis. Endocrine reviews 21:115-137
Rochefort GY, Pallu S, Benhamou CL 2010 Osteocyte: the
unrecognized side of bone tissue. Osteoporosis international
21:1457-1469
Hamdy NAT 2007 Novel approaches to living bone. In: Roux C ed.
The living skeleton. France: Wolters Kluever Health
Lerner UH 2000 Osteoclast formation and resorption. Matrix
biology : journal of the International Society for Matrix Biology
19:107-120
Kular J, Tickner J, Chim SM, Xu J 2012 An overview of the
regulation of bone remodelling at the cellular level. Clinical
biochemistry 45:863-873
Ross FP 2013 Osteoclast biology and bone resorption. In: Rosen CJ
ed. Primer on the metabolic bone diseases and disorders of mineral
metabolism. Singapore: John Wiley & Sons, Inc
Elefteriou FK, G. 2013 Neuronal regulation of bone remodeling. In:
Rosen CJ ed. Primer on the metabolic bone diseases and disorders of
mineral metabolism. Singapore: John Wiley and sons, inc.
Seeman E 1997 The living skeletonThe size, shape, spatial
distribution and strength of bone in adulthood. In: Roux C ed. The
living skeleton. France: Wolters Kluwer Health
Martin TJ, Seeman E 2008 Bone remodelling: its local regulation
and the emergence of bone fragility. Best practice & research.
Clinical endocrinology & metabolism 22:701-722
Khosla S, Westendorf JJ, Oursler MJ 2008 Building bone to
reverse osteoporosis and repair fractures. The Journal of clinical
investigation 118:421-428
Sambrook P, Cooper C 2006 Osteoporosis. Lancet 367:2010-2018
36
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
Zuo C, Huang Y, Bajis R, Sahih M, Li YP, Dai K, Zhang X 2012
Osteoblastogenesis regulation signals in bone remodeling.
Osteoporosis international 23:1653-1663
1993 Consensus development conference: diagnosis, prophylaxis,
and treatment of osteoporosis. The American journal of medicine
94:646-650
Kanis JA, Johnell O, Oden A, Sembo I, Redlund-Johnell I,
Dawson A, De Laet C, Jonsson B 2000 Long-term risk of
osteoporotic fracture in Malmo. Osteoporosis international 11:669674
Cummings SR, Melton LJ 2002 Epidemiology and outcomes of
osteoporotic fractures. Lancet 359:1761-1767
Boonen S 2007 Bone remodelling, bone loss and bone fragility in old
age. In: C R ed. The living skeleton. France: Wolters Kluwer Health
Harvey ND, E.; Cooper, C. 2013 The epidemiology of osteoporotic
fractures. In: Rosen CJ ed. Primer on the metabolic bone diseases and
disorders of mineral metabolism. Singapore: John Wiley & Sons
Kaufman JM, Reginster JY, Boonen S, Brandi ML, Cooper C,
Dere W, Devogelaer JP, Diez-Perez A, Kanis JA, McCloskey E,
Mitlak B, Orwoll E, Ringe JD, Weryha G, Rizzoli R 2013
Treatment of osteoporosis in men. Bone 53:134-144
Kanis JA, Delmas P, Burckhardt P, Cooper C, Torgerson D 1997
Guidelines for diagnosis and management of osteoporosis. The
European Foundation for Osteoporosis and Bone Disease.
Osteoporosis international 7:390-406
Johnell O, Kanis JA, Oden A, Johansson H, De Laet C, Delmas
P, Eisman JA, Fujiwara S, Kroger H, Mellstrom D, Meunier PJ,
Melton LJ, 3rd, O'Neill T, Pols H, Reeve J, Silman A,
Tenenhouse A 2005 Predictive value of BMD for hip and other
fractures. Journal of bone and mineral research 20:1185-1194
Cummings SR, Nevitt MC, Browner WS, Stone K, Fox KM,
Ensrud KE, Cauley J, Black D, Vogt TM 1995 Risk factors for hip
fracture in white women. Study of Osteoporotic Fractures Research
Group. N Engl J Med 332:767-773
Cummings SR, Black DM, Nevitt MC, Browner W, Cauley J,
Ensrud K, Genant HK, Palermo L, Scott J, Vogt TM 1993 Bone
density at various sites for prediction of hip fractures. The Study of
Osteoporotic Fractures Research Group. Lancet 341:72-75
Kanis JA, Johnell O, De Laet C, Johansson H, Oden A, Delmas
P, Eisman J, Fujiwara S, Garnero P, Kroger H, McCloskey EV,
Mellstrom D, Melton LJ, Pols H, Reeve J, Silman A, Tenenhouse
A 2004 A meta-analysis of previous fracture and subsequent fracture
risk. Bone 35:375-382
Kanis JA, Johansson H, Oden A, Johnell O, de Laet C, Melton
IL, Tenenhouse A, Reeve J, Silman AJ, Pols HA, Eisman JA,
37
Bone density, bone geometry and bone development in young men
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
McCloskey EV, Mellstrom D 2004 A meta-analysis of prior
corticosteroid use and fracture risk. Journal of bone and mineral
research 19:893-899
Kanis JA, Johansson H, Oden A, Johnell O, De Laet C, Eisman
JA, McCloskey EV, Mellstrom D, Melton LJ, 3rd, Pols HA,
Reeve J, Silman AJ, Tenenhouse A 2004 A family history of
fracture and fracture risk: a meta-analysis. Bone 35:1029-1037
Kanis JA, Johnell O, Oden A, Johansson H, De Laet C, Eisman
JA, Fujiwara S, Kroger H, McCloskey EV, Mellstrom D, Melton
LJ, Pols H, Reeve J, Silman A, Tenenhouse A 2005 Smoking and
fracture risk: a meta-analysis. Osteoporosis international 16:155-162
Kanis JA, Johansson H, Johnell O, Oden A, De Laet C, Eisman
JA, Pols H, Tenenhouse A 2005 Alcohol intake as a risk factor for
fracture. Osteoporosis international 16:737-742
Kanis JA 2002 Diagnosis of osteoporosis and assessment of fracture
risk. Lancet 359:1929-1936
De Laet C, Kanis JA, Oden A, Johanson H, Johnell O, Delmas P,
Eisman JA, Kroger H, Fujiwara S, Garnero P, McCloskey EV,
Mellstrom D, Melton LJ, 3rd, Meunier PJ, Pols HA, Reeve J,
Silman A, Tenenhouse A 2005 Body mass index as a predictor of
fracture risk: a meta-analysis. Osteoporosis international 16:13301338
Kanis JA, Oden A, Johansson H, Borgstrom F, Strom O,
McCloskey E 2009 FRAX and its applications to clinical practice.
Bone 44:734-743
Stagi S, Cavalli L, Iurato C, Seminara S, Brandi ML, de Martino
M 2013 Bone metabolism in children and adolescents: main
characteristics of the determinants of peak bone mass. Clinical cases
in mineral and bone metabolism 10:172-179
Bachrach LK 2001 Acquisition of optimal bone mass in childhood
and adolescence. Trends Endocrinol Metab 12:22-28
Bonjour JP CT, Ferrari S, Rizzoli R 2007 Bone and its
characteristics during childhood and adolescence up to peak bone
mass. In: C R ed. The living skeleton. France: Wolters Kluwer
Health
Jurimae J 2010 Interpretation and application of bone turnover
markers in children and adolescents. Current opinion in pediatrics
22:494-500
Bonjour JP, Chevalley T 2014 Pubertal timing, bone acquisition,
and risk of fracture throughout life. Endocrine reviews 35:820-847
Bonjour JP, Theintz G, Law F, Slosman D, Rizzoli R 1994 Peak
bone mass. Osteoporosis international 4 Suppl 1:7-13
Seeman E 2002 Pathogenesis of bone fragility in women and men.
Lancet 359:1841-1850
38
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
Baxter-Jones AD, Faulkner RA, Forwood MR, Mirwald RL,
Bailey DA 2011 Bone mineral accrual from 8 to 30 years of age: an
estimation of peak bone mass. Journal of bone and mineral research
26:1729-1739
Boot AM, de Ridder MA, van der Sluis IM, van Slobbe I,
Krenning EP, de Muinck Keizer-Schrama SM 2009 Peak bone
mineral density, lean body mass and fractures. Bone
Xu L, Nicholson P, Wang Q, Alen M, Cheng S 2009 Bone and
muscle development during puberty in girls: a seven-year
longitudinal study. Journal of bone and mineral research 24:16931698
Wren TA, Kim PS, Janicka A, Sanchez M, Gilsanz V 2007
Timing of peak bone mass: discrepancies between CT and DXA. The
Journal of clinical endocrinology and metabolism 92:938-941
Slosman DO, Rizzoli R, Pichard C, Donath A, Bonjour JP 1994
Longitudinal measurement of regional and whole body bone mass in
young healthy adults. Osteoporosis international 4:185-190
Recker RR, Davies KM, Hinders SM, Heaney RP, Stegman MR,
Kimmel DB 1992 Bone gain in young adult women. Jama 268:24032408
Lorentzon M, Mellstrom D, Ohlsson C 2005 Age of attainment of
peak bone mass is site specific in Swedish men--The GOOD study.
Journal of bone and mineral research 20:1223-1227
Lin YC, Lyle RM, Weaver CM, McCabe LD, McCabe GP,
Johnston CC, Teegarden D 2003 Peak spine and femoral neck bone
mass in young women. Bone 32:546-553
Henry YM, Fatayerji D, Eastell R 2004 Attainment of peak bone
mass at the lumbar spine, femoral neck and radius in men and
women: relative contributions of bone size and volumetric bone
mineral density. Osteoporosis international 15:263-273
Stewart TL, Ralston SH 2000 Role of genetic factors in the
pathogenesis of osteoporosis. The Journal of endocrinology 166:235245
Wang MC, Crawford PB, Hudes M, Van Loan M, Siemering K,
Bachrach LK 2003 Diet in midpuberty and sedentary activity in
prepuberty predict peak bone mass. The American journal of clinical
nutrition 77:495-503
Rizzoli R, Bianchi ML, Garabedian M, McKay HA, Moreno LA
2010 Maximizing bone mineral mass gain during growth for the
prevention of fractures in the adolescents and the elderly. Bone
46:294-305
Winzenberg TM, Shaw K, Fryer J, Jones G 2006 Calcium
supplementation for improving bone mineral density in children. The
Cochrane database of systematic reviews:CD005119
39
Bone density, bone geometry and bone development in young men
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
Winzenberg T, Shaw K, Fryer J, Jones G 2006 Effects of calcium
supplementation on bone density in healthy children: meta-analysis
of randomised controlled trials. Bmj 333:775
Huncharek M, Muscat J, Kupelnick B 2008 Impact of dairy
products and dietary calcium on bone-mineral content in children:
results of a meta-analysis. Bone 43:312-321
Sopher AB, Fennoy I, Oberfield SE 2015 An update on childhood
bone health: mineral accrual, assessment and treatment. Current
opinion in endocrinology, diabetes, and obesity 22:35-40
Wang TJ, Zhang F, Richards JB, Kestenbaum B, van Meurs JB,
Berry D, Kiel DP, Streeten EA, Ohlsson C, Koller DL, Peltonen
L, Cooper JD, O'Reilly PF, Houston DK, Glazer NL, Vandenput
L, Peacock M, Shi J, Rivadeneira F, McCarthy MI, Anneli P, de
Boer IH, Mangino M, Kato B, Smyth DJ, Booth SL, Jacques PF,
Burke GL, Goodarzi M, Cheung CL, Wolf M, Rice K, Goltzman
D, Hidiroglou N, Ladouceur M, Wareham NJ, Hocking LJ, Hart
D, Arden NK, Cooper C, Malik S, Fraser WD, Hartikainen AL,
Zhai G, Macdonald HM, Forouhi NG, Loos RJ, Reid DM,
Hakim A, Dennison E, Liu Y, Power C, Stevens HE, Jaana L,
Vasan RS, Soranzo N, Bojunga J, Psaty BM, Lorentzon M,
Foroud T, Harris TB, Hofman A, Jansson JO, Cauley JA,
Uitterlinden AG, Gibson Q, Jarvelin MR, Karasik D, Siscovick
DS, Econs MJ, Kritchevsky SB, Florez JC, Todd JA, Dupuis J,
Hypponen E, Spector TD 2010 Common genetic determinants of
vitamin D insufficiency: a genome-wide association study. Lancet
376:180-188
Spiro A, Buttriss JL 2014 Vitamin D: An overview of vitamin D
status and intake in Europe. Nutrition bulletin / BNF 39:322-350
Winzenberg TM, Powell S, Shaw KA, Jones G 2010 Vitamin D
supplementation for improving bone mineral density in children. The
Cochrane database of systematic reviews:CD006944
Winzenberg T, Powell S, Shaw KA, Jones G 2011 Effects of
vitamin D supplementation on bone density in healthy children:
systematic review and meta-analysis. Bmj 342:c7254
Pekkinen M, Viljakainen H, Saarnio E, Lamberg-Allardt C,
Makitie O 2012 Vitamin D is a major determinant of bone mineral
density at school age. PloS one 7:e40090
Gunter KB, Almstedt HC, Janz KF 2012 Physical activity in
childhood may be the key to optimizing lifespan skeletal health.
Exercise and sport sciences reviews 40:13-21
Tenforde AS, Fredericson M 2011 Influence of sports participation
on bone health in the young athlete: a review of the literature. PM &
R : the journal of injury, function, and rehabilitation 3:861-867
40
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
Scofield KL, Hecht S 2012 Bone health in endurance athletes:
runners, cyclists, and swimmers. Current sports medicine reports
11:328-334
Specker B, Minett M 2013 Can physical activity improve peak bone
mass? Current osteoporosis reports 11:229-236
MacKelvie KJ, Khan KM, McKay HA 2002 Is there a critical
period for bone response to weight-bearing exercise in children and
adolescents? a systematic review. British journal of sports medicine
36:250-257; discussion 257
Hind K, Burrows M 2007 Weight-bearing exercise and bone
mineral accrual in children and adolescents: a review of controlled
trials. Bone 40:14-27
Detter F, Rosengren BE, Dencker M, Lorentzon M, Nilsson JA,
Karlsson MK 2014 A 6-year exercise program improves skeletal
traits without affecting fracture risk: a prospective controlled study in
2621 children. Journal of bone and mineral research 29:1325-1336
Nilsson M, Ohlsson C, Mellstrom D, Lorentzon M 2009 Previous
sport activity during childhood and adolescence is associated with
increased cortical bone size in young adult men. Journal of bone and
mineral research 24:125-133
Duckham RL, Baxter-Jones AD, Johnston JD, Vatanparast H,
Cooper D, Kontulainen S 2014 Does physical activity in
adolescence have site-specific and sex-specific benefits on young
adult bone size, content, and estimated strength? Journal of bone and
mineral research 29:479-486
Baxter-Jones AD, Kontulainen SA, Faulkner RA, Bailey DA
2008 A longitudinal study of the relationship of physical activity to
bone mineral accrual from adolescence to young adulthood. Bone
43:1101-1107
Nilsson M, Ohlsson C, Oden A, Mellstrom D, Lorentzon M 2012
Increased physical activity is associated with enhanced development
of peak bone mass in men: a five-year longitudinal study. Journal of
bone and mineral research 27:1206-1214
Ward KD, Klesges RC 2001 A meta-analysis of the effects of
cigarette smoking on bone mineral density. Calcified tissue
international 68:259-270
Vestergaard P, Mosekilde L 2003 Fracture risk associated with
smoking: a meta-analysis. Journal of internal medicine 254:572-583
Law MR, Hackshaw AK 1997 A meta-analysis of cigarette
smoking, bone mineral density and risk of hip fracture: recognition of
a major effect. Bmj 315:841-846
Winther A, Dennison E, Ahmed LA, Furberg AS, Grimnes G,
Jorde R, Gjesdal CG, Emaus N 2014 The Tromso Study: Fit
Futures: a study of Norwegian adolescents' lifestyle and bone health.
Archives of osteoporosis 9:185
41
Bone density, bone geometry and bone development in young men
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
Eleftheriou KI, Rawal JS, James LE, Payne JR, Loosemore M,
Pennell DJ, World M, Drenos F, Haddad FS, Humphries SE,
Sanders J, Montgomery HE 2013 Bone structure and geometry in
young men: the influence of smoking, alcohol intake and physical
activity. Bone 52:17-26
Dorn LD, Beal SJ, Kalkwarf HJ, Pabst S, Noll JG, Susman EJ
2013 Longitudinal impact of substance use and depressive symptoms
on bone accrual among girls aged 11-19 years. The Journal of
adolescent health 52:393-399
Lorentzon M, Mellstrom D, Haug E, Ohlsson C 2007 Smoking is
associated with lower bone mineral density and reduced cortical
thickness in young men. The Journal of clinical endocrinology and
metabolism 92:497-503
Rudang R, Darelid A, Nilsson M, Nilsson S, Mellstrom D,
Ohlsson C, Lorentzon M 2012 Smoking is associated with impaired
bone mass development in young adult men: a 5-year longitudinal
study. Journal of bone and mineral research 27:2189-2197
Chevalley T, Bonjour JP, Ferrari S, Rizzoli R 2009 Deleterious
effect of late menarche on distal tibia microstructure in healthy 20year-old and premenopausal middle-aged women. Journal of bone
and mineral research 24:144-152
Chevalley T, Bonjour JP, Ferrari S, Rizzoli R 2008 Influence of
age at menarche on forearm bone microstructure in healthy young
women. The Journal of clinical endocrinology and metabolism
93:2594-2601
Gilsanz V, Chalfant J, Kalkwarf H, Zemel B, Lappe J, Oberfield
S, Shepherd J, Wren T, Winer K 2011 Age at onset of puberty
predicts bone mass in young adulthood. The Journal of pediatrics
158:100-105, 105 e101-102
Jackowski SA, Erlandson MC, Mirwald RL, Faulkner RA,
Bailey DA, Kontulainen SA, Cooper DM, Baxter-Jones AD 2011
Effect of maturational timing on bone mineral content accrual from
childhood to adulthood: evidence from 15 years of longitudinal data.
Bone 48:1178-1185
Kindblom JM, Lorentzon M, Norjavaara E, Hellqvist A, Nilsson
S, Mellstrom D, Ohlsson C 2006 Pubertal timing predicts previous
fractures and BMD in young adult men: the GOOD study. Journal of
bone and mineral research 21:790-795
Jones IE, Williams SM, Dow N, Goulding A 2002 How many
children remain fracture-free during growth? a longitudinal study of
children and adolescents participating in the Dunedin
Multidisciplinary Health and Development Study. Osteoporosis
international 13:990-995
Cooper C, Dennison EM, Leufkens HG, Bishop N, van Staa TP
2004 Epidemiology of childhood fractures in Britain: a study using
42
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
the general practice research database. Journal of bone and mineral
research 19:1976-1981
Landin LA 1997 Epidemiology of children's fractures. J Pediatr
Orthop B 6:79-83
Goulding A, Jones IE, Taylor RW, Williams SM, Manning PJ
2001 Bone mineral density and body composition in boys with distal
forearm fractures: a dual-energy x-ray absorptiometry study. The
Journal of pediatrics 139:509-515
Goulding A, Cannan R, Williams SM, Gold EJ, Taylor RW,
Lewis-Barned NJ 1998 Bone mineral density in girls with forearm
fractures. Journal of bone and mineral research 13:143-148
Flynn J, Foley S, Jones G 2007 Can BMD assessed by DXA at age
8 predict fracture risk in boys and girls during puberty?: an eight-year
prospective study. Journal of bone and mineral research 22:14631467
Clark EM, Tobias JH, Ness AR 2006 Association between bone
density and fractures in children: a systematic review and metaanalysis. Pediatrics 117:e291-297
Clark EM, Ness AR, Bishop NJ, Tobias JH 2006 Association
between bone mass and fractures in children: a prospective cohort
study. Journal of bone and mineral research 21:1489-1495
Ferrari SL, Chevalley T, Bonjour JP, Rizzoli R 2006 Childhood
fractures are associated with decreased bone mass gain during
puberty: an early marker of persistent bone fragility? Journal of bone
and mineral research 21:501-507
Buttazzoni C, Rosengren BE, Tveit M, Landin L, Nilsson JA,
Karlsson MK 2013 Does a childhood fracture predict low bone mass
in young adulthood? A 27-year prospective controlled study. Journal
of bone and mineral research 28:351-359
Pye SR, Tobias J, Silman AJ, Reeve J, O'Neill TW 2009
Childhood fractures do not predict future fractures: results from the
European Prospective Osteoporosis Study. Journal of bone and
mineral research 24:1314-1318
Landin LA 1983 Fracture patterns in children. Analysis of 8,682
fractures with special reference to incidence, etiology and secular
changes in a Swedish urban population 1950-1979. Acta Orthop
Scand Suppl 202:1-109
Hagino H, Yamamoto K, Teshima R, Kishimoto H, Nakamura T
1990 Fracture incidence and bone mineral density of the distal radius
in Japanese children. Arch Orthop Trauma Surg 109:262-264
Mackey DC, Lui LY, Cawthon PM, Bauer DC, Nevitt MC,
Cauley JA, Hillier TA, Lewis CE, Barrett-Connor E, Cummings
SR 2007 High-trauma fractures and low bone mineral density in
older women and men. Jama 298:2381-2388
43
Bone density, bone geometry and bone development in young men
101.
102.
103.
104.
105.
106.
107.
108.
109.
110.
Fournier PE, Rizzoli R, Slosman DO, Theintz G, Bonjour JP
1997 Asynchrony between the rates of standing height gain and bone
mass accumulation during puberty. Osteoporosis international 7:525532
Faulkner RA, Davison KS, Bailey DA, Mirwald RL, BaxterJones AD 2006 Size-corrected BMD decreases during peak linear
growth: implications for fracture incidence during adolescence.
Journal of bone and mineral research 21:1864-1870
Vasikaran S, Eastell R, Bruyere O, Foldes AJ, Garnero P,
Griesmacher A, McClung M, Morris HA, Silverman S, Trenti T,
Wahl DA, Cooper C, Kanis JA 2011 Markers of bone turnover for
the prediction of fracture risk and monitoring of osteoporosis
treatment: a need for international reference standards. Osteoporosis
international 22:391-420
Lee J, Vasikaran S 2012 Current recommendations for laboratory
testing and use of bone turnover markers in management of
osteoporosis. Ann Lab Med 32:105-112
Camacho PM, Lopez NA 2008 Use of biochemical markers of bone
turnover in the management of postmenopausal osteoporosis. Clin
Chem Lab Med 46:1345-1357
Biver E 2012 Use of bone turnover markers in clinical practice.
Current opinion in endocrinology, diabetes, and obesity 19:468-473
Tamaki J, Iki M, Kadowaki E, Sato Y, Chiba Y, Akiba T,
Matsumoto T, Nishino H, Kagamimori S, Kagawa Y, Yoneshima
H, Group JS 2013 Biochemical markers for bone turnover predict
risk of vertebral fractures in postmenopausal women over 10 years:
the Japanese Population-based Osteoporosis (JPOS) Cohort Study.
Osteoporosis international 24:887-897
Johansson H, Oden A, Kanis JA, McCloskey EV, Morris HA,
Cooper C, Vasikaran S, Turnover I-IJWGoSoBMoB 2014 A
meta-analysis of reference markers of bone turnover for prediction of
fracture. Calcified tissue international 94:560-567
Chubb SA, Byrnes E, Manning L, Beilby JP, Ebeling PR,
Vasikaran SD, Golledge J, Flicker L, Yeap BB 2015 Reference
intervals for bone turnover markers and their association with
incident hip fractures in older men: the health in men study. The
Journal of clinical endocrinology and metabolism 100:90-99
Brown JP, Albert C, Nassar BA, Adachi JD, Cole D, Davison KS,
Dooley KC, Don-Wauchope A, Douville P, Hanley DA, Jamal SA,
Josse R, Kaiser S, Krahn J, Krause R, Kremer R, Lepage R,
Letendre E, Morin S, Ooi DS, Papaioaonnou A, Ste-Marie LG
2009 Bone turnover markers in the management of postmenopausal
osteoporosis. Clinical biochemistry 42:929-942
44
111.
112.
113.
114.
115.
116.
117.
118.
119.
120.
121.
Szulc P, Seeman E, Delmas PD 2000 Biochemical measurements of
bone turnover in children and adolescents. Osteoporosis international
11:281-294
Tamiya M, Tokunaga S, Okada H, Suzuki H, Kobayashi M,
Sasada S, Okamoto N, Morishita N, Matsuura Y, Miyamoto N,
Hattori M, Taira K, Daga H, Takeda K, Hirashima T 2013
Prospective study of urinary and serum cross-linked N-telopeptide of
type I collagen (NTx) for diagnosis of bone metastasis in patients
with lung cancer. Clinical lung cancer 14:364-369
Mora S, Pitukcheewanont P, Kaufman FR, Nelson JC, Gilsanz V
1999 Biochemical markers of bone turnover and the volume and the
density of bone in children at different stages of sexual development.
Journal of bone and mineral research 14:1664-1671
Gracia-Marco L, Vicente-Rodriguez G, Valtuena J, Rey-Lopez
JP, Diaz Martinez AE, Mesana MI, Widhalm K, Ruiz JR,
Gonzalez-Gross M, Castillo MJ, Moreno LA 2010 Bone mass and
bone metabolism markers during adolescence: The HELENA Study.
Horm Res Paediatr 74:339-350
Fortes CM, Goldberg TB, Kurokawa CS, Silva CC, Moretto MR,
Biason TP, Teixeira AS, de Carvalho Nunes HR 2014
Relationship between chronological and bone ages and pubertal stage
of breasts with bone biomarkers and bone mineral density in
adolescents. Jornal de pediatria 90:624-631
Blake G. AJ, Bishop N. 2013 DXA in adults and children. In: CJ R
ed. Primer on the metabolic bon diseases and disorders of mineral
metabolism. 8 ed. Singapore: John Wiley & Sons, Inc.
Kanis JA, Melton LJ, 3rd, Christiansen C, Johnston CC,
Khaltaev N 1994 The diagnosis of osteoporosis. Journal of bone and
mineral research 9:1137-1141
Kanis JA, Johnell O, Oden A, Jonsson B, De Laet C, Dawson A
2000 Risk of hip fracture according to the World Health
Organization criteria for osteopenia and osteoporosis. Bone 27:585590
Gluer CC 2013 Quantitative computed tomography in children and
adults. In: Rosen CJ ed. Primer on the metabolic bone diseases and
disorders of mineral metabolism. 8 ed. Singapore: John Wiley &
Sons, Inc.
Lee VR, Blew RM, Farr JN, Tomas R, Lohman TG, Going SB
2013 Estimation of whole body fat from appendicular soft tissue
from peripheral quantitative computed tomography in adolescent
girls. International journal of body composition research 11:1-8
Engelke K, Adams JE, Armbrecht G, Augat P, Bogado CE,
Bouxsein ML, Felsenberg D, Ito M, Prevrhal S, Hans DB,
Lewiecki EM 2008 Clinical use of quantitative computed
tomography and peripheral quantitative computed tomography in the
45
Bone density, bone geometry and bone development in young men
122.
123.
124.
125.
126.
127.
128.
129.
130.
131.
132.
management of osteoporosis in adults: the 2007 ISCD Official
Positions. Journal of clinical densitometry : the official journal of the
International Society for Clinical Densitometry 11:123-162
Karlberg J, Fryer JG, Engstrom I, Karlberg P 1987 Analysis of
linear growth using a mathematical model. II. From 3 to 21 years of
age. Acta Paediatr Scand Suppl 337:12-29
Karlberg J 1987 On the modelling of human growth. Stat Med
6:185-192
Liu YX, Wikland KA, Karlberg J 2000 New reference for the age
at childhood onset of growth and secular trend in the timing of
puberty in Swedish. Acta Paediatr 89:637-643
Schoenau E, Neu CM, Rauch F, Manz F 2001 The development of
bone strength at the proximal radius during childhood and
adolescence. The Journal of clinical endocrinology and metabolism
86:613-618
Darelid A, Ohlsson C, Rudang R, Kindblom JM, Mellstrom D,
Lorentzon M 2010 Trabecular volumetric bone mineral density is
associated with previous fracture during childhood and adolescence
in males: the GOOD study. Journal of bone and mineral research
25:537-544
Lorentzon M, Mellstrom D, Ohlsson C 2005 Association of
amount of physical activity with cortical bone size and trabecular
volumetric BMD in young adult men: the GOOD study. Journal of
bone and mineral research 20:1936-1943
Bailey DA, Wedge JH, McCulloch RG, Martin AD, Bernhardson
SC 1989 Epidemiology of fractures of the distal end of the radius in
children as associated with growth. The Journal of bone and joint
surgery. American volume 71:1225-1231
Taes Y, Lapauw B, Griet V, De Bacquer D, Goemaere S,
Zmierczak H, Kaufman JM 2010 Prevalent fractures are related to
cortical bone geometry in young healthy men at age of peak bone
mass. Journal of bone and mineral research 25:1433-1440
Chevalley T, Bonjour JP, van Rietbergen B, Ferrari S, Rizzoli R
2011 Fractures during childhood and adolescence in healthy boys:
relation with bone mass, microstructure, and strength. The Journal of
clinical endocrinology and metabolism 96:3134-3142
Chevalley T, Bonjour JP, van Rietbergen B, Rizzoli R, Ferrari S
2012 Fractures in healthy females followed from childhood to early
adulthood are associated with later menarcheal age and with impaired
bone microstructure at peak bone mass. The Journal of clinical
endocrinology and metabolism 97:4174-4181
Farr JN, Tomas R, Chen Z, Lisse JR, Lohman TG, Going SB
2011 Lower trabecular volumetric BMD at metaphyseal regions of
weight-bearing bones is associated with prior fracture in young girls.
Journal of bone and mineral research 26:380-387
46
133.
134.
135.
136.
137.
138.
139.
140.
141.
142.
Rudang R, Darelid A, Nilsson M, Mellstrom D, Ohlsson C,
Lorentzon M 2013 X-ray-verified fractures are associated with finite
element analysis-derived bone strength and trabecular microstructure
in young adult men. Journal of bone and mineral research 28:23052316
Ohlsson C, Darelid A, Nilsson M, Melin J, Mellstrom D,
Lorentzon M 2011 Cortical consolidation due to increased
mineralization and endosteal contraction in young adult men: a fiveyear longitudinal study. The Journal of clinical endocrinology and
metabolism 96:2262-2269
Berger C, Goltzman D, Langsetmo L, Joseph L, Jackson S,
Kreiger N, Tenenhouse A, Davison KS, Josse RG, Prior JC,
Hanley DA 2010 Peak bone mass from longitudinal data:
implications for the prevalence, pathophysiology, and diagnosis of
osteoporosis. Journal of bone and mineral research 25:1948-1957
Bachrach LK, Hastie T, Wang MC, Narasimhan B, Marcus R
1999 Bone mineral acquisition in healthy Asian, Hispanic, black, and
Caucasian youth: a longitudinal study. The Journal of clinical
endocrinology and metabolism 84:4702-4712
Khosla S, Melton LJ, 3rd, Atkinson EJ, O'Fallon WM 2001
Relationship of serum sex steroid levels to longitudinal changes in
bone density in young versus elderly men. The Journal of clinical
endocrinology and metabolism 86:3555-3561
Emaus N, Berntsen GK, Joakimsen RM, Fonnebo V 2005
Longitudinal changes in forearm bone mineral density in women and
men aged 25-44 years: the Tromso study: a population-based study.
Am J Epidemiol 162:633-643
Darelid A, Ohlsson C, Nilsson M, Kindblom JM, Mellstrom D,
Lorentzon M 2012 Catch up in bone acquisition in young adult men
with late normal puberty. Journal of bone and mineral research
27:2198-2207
Tuppurainen M, Kroger H, Saarikoski S, Honkanen R, Alhava E
1995 The effect of gynecological risk factors on lumbar and femoral
bone mineral density in peri- and postmenopausal women. Maturitas
21:137-145
Silman AJ 2003 Risk factors for Colles' fracture in men and women:
results from the European Prospective Osteoporosis Study.
Osteoporosis international : a journal established as result of
cooperation between the European Foundation for Osteoporosis and
the National Osteoporosis Foundation of the USA 14:213-218
Roy DK, O'Neill TW, Finn JD, Lunt M, Silman AJ, Felsenberg
D, Armbrecht G, Banzer D, Benevolenskaya LI, Bhalla A,
Bruges Armas J, Cannata JB, Cooper C, Dequeker J, Diaz MN,
Eastell R, Yershova OB, Felsch B, Gowin W, Havelka S,
Hoszowski K, Ismail AA, Jajic I, Janott I, Johnell O, Kanis JA,
47
Bone density, bone geometry and bone development in young men
143.
144.
145.
146.
147.
148.
149.
150.
151.
152.
Kragl G, Lopez Vaz A, Lorenc R, Lyritis G, Masaryk P, Matthis
C, Miazgowski T, Gennari C, Pols HA, Poor G, Raspe HH, Reid
DM, Reisinger W, Scheidt-Nave C, Stepan JJ, Todd CJ, Weber
K, Woolf AD, Reeve J 2003 Determinants of incident vertebral
fracture in men and women: results from the European Prospective
Osteoporosis Study (EPOS). Osteoporosis international 14:19-26
Johnell O, Gullberg B, Kanis JA, Allander E, Elffors L,
Dequeker J, Dilsen G, Gennari C, Lopes Vaz A, Lyritis G, et al.
1995 Risk factors for hip fracture in European women: the MEDOS
Study. Mediterranean Osteoporosis Study. Journal of bone and
mineral research 10:1802-1815
Fox KM, Magaziner J, Sherwin R, Scott JC, Plato CC, Nevitt M,
Cummings S 1993 Reproductive correlates of bone mass in elderly
women. Study of Osteoporotic Fractures Research Group. Journal of
bone and mineral research 8:901-908
Rosenthal DI, Mayo-Smith W, Hayes CW, Khurana JS, Biller
BM, Neer RM, Klibanski A 1989 Age and bone mass in
premenopausal women. Journal of bone and mineral research 4:533538
Ito M, Yamada M, Hayashi K, Ohki M, Uetani M, Nakamura T
1995 Relation of early menarche to high bone mineral density.
Calcified tissue international 57:11-14
Darelid A, Nilsson M, Kindblom JM, Mellstrom D, Ohlsson C,
Lorentzon M 2015 Bone Turnover Markers Predict Bone Mass
Development in Young Adult Men: A Five Year Longitudinal Study.
The Journal of clinical endocrinology and metabolism:jc20143947
Sherar LB, Baxter-Jones AD, Mirwald RL 2004 Limitations to the
use of secondary sex characteristics for gender comparisons. Ann
Hum Biol 31:586-593
van Coeverden SC, Netelenbos JC, de Ridder CM, Roos JC,
Popp-Snijders C, Delemarre-van de Waal HA 2002 Bone
metabolism markers and bone mass in healthy pubertal boys and
girls. Clin Endocrinol (Oxf) 57:107-116
Johansen JS, Giwercman A, Hartwell D, Nielsen CT, Price PA,
Christiansen C, Skakkebaek NE 1988 Serum bone Gla-protein as a
marker of bone growth in children and adolescents: correlation with
age, height, serum insulin-like growth factor I, and serum
testosterone. The Journal of clinical endocrinology and metabolism
67:273-278
Kanbur NO, Derman O, Sen TA, Kinik E 2002 Osteocalcin. A
biochemical marker of bone turnover during puberty. Int J Adolesc
Med Health 14:235-244
Donescu OS, Battie MC, Videman T, Risteli J, Eyre D 2006 The
predictive role of bone turnover markers for BMD in middle-aged
men. Aging Male 9:97-102
48
153.
154.
155.
156.
Syvaoja HJ, Kantomaa MT, Ahonen T, Hakonen H,
Kankaanpaa A, Tammelin TH 2013 Physical activity, sedentary
behavior, and academic performance in Finnish children. Medicine
and science in sports and exercise 45:2098-2104
Pate RR, Mitchell JA, Byun W, Dowda M 2011 Sedentary
behaviour in youth. British journal of sports medicine 45:906-913
Myer GD, Faigenbaum AD, Stracciolini A, Hewett TE, Micheli
LJ, Best TM 2013 Exercise deficit disorder in youth: a paradigm
shift toward disease prevention and comprehensive care. Current
sports medicine reports 12:248-255
Bachrach LK 2000 Making an impact on pediatric bone health. The
Journal of pediatrics 136:137-139
49